Decibio webinar "Oncologist's Role in Digital Pathology Revolution"

https://www.linkedin.com/posts/decibio_digitalpathology-precisionmedicine-oncology-ugcPost-7240012342288130051-bZ4e/?utm_source=share&utm_medium=member_ios

 

https://www.decibio.com/insights/the-oncologists-role-in-the-digital-pathology-revolution-webinar

This webinar was recorded on Thursday, 5th September 2024.

Digital pathology tools, such as predictive and prognostic algorithms, can help facilitate increased efficiencies and improved patient outcomes. To date, conversations around digital pathology tools have understandably focused on the pathologist and lab. However, emerging DP tools are increasingly targeting clinical questions (rather than pathologist efficiencies), creating opportunities to include oncologists in discussions.

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During this webinar, we will discuss different perspectives on the hurdles to tool adoption, offer suggestions on how we can overcome these, and share insights from a lab medicine perspective, where we believe digital tools, such as workflow and diagnostics tools, can improve health outcomes.

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Speakers:

• Charles Gaulin, MD, Hematologist Oncologist at Dartmouth

• Joseph Annunziata, MD, Medical Director, Molecular Pathologist

• Omar Perez, PhD, Head of Medical Diagnostics at AstraZeneca

• Heinz-Josef Klümpen, MD, Medical Oncologist, Consultant at Amsterdam University Medical Center

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Moderators:

• Katie Maloney, DeciBio Consulting
• Esther Abels, SolarisRTC

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Learn more about DeciBio's Digital Pathology Market Report here: https://www.decibio.com/product/digital-pathology-market-report

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View the webinar recording below:

*Note that due to an error with Zoom—Katie Maloney has been incorrectly labeled as Omar Perez in the recording.

View the Webinar Recording

In cased you missed our webinar, "The Oncologist's Role in the Digital Pathology Revolution" last week, you can now watch the full session on demand on our website here: https://lnkd.in/gX3TZmws

Moderated by Esther Abels and Katie Maloney

Thank you to our panelists Omar Perez, Joseph Annunziata, M.D., Heinz-Josef Klümpen, and Charles Gaulin for sharing their invaluable perspectives and to our engaged audience for your thought-provoking questions.

hashtag#DigitalPathology hashtag#PrecisionMedicine hashtag#Oncology

tagcsd taglungevity

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Decibio Webinar Review: Integrating Oncologists into the Digital Pathology Revolution

Decibio’s September 5, 2024 webinar, The Role of the Oncologist in the Digital Pathology Revolution, brought together key thought leaders from oncology, pathology, and biopharma to discuss the future of digital pathology. The discussion provided a comprehensive look at how emerging tools, such as diagnostic algorithms and digital slide sharing, are breaking the traditional boundaries of pathology labs and increasingly involving oncologists in the conversation.

Dr. Charles Gaulin, a hematologist oncologist from Dartmouth, began by acknowledging that while digital pathology (DP) has primarily focused on pathology lab efficiencies, the field is shifting. Today’s digital tools are targeting clinical questions that can directly improve patient outcomes, and oncologists now have a growing role to play in adopting and using these technologies. Gaulin pointed out that for oncologists, the primary hurdle remains diagnostic delays caused by information bottlenecks. He noted that approximately half of his patients come to him with incomplete pathology information, requiring additional review and sometimes delaying the start of life-saving therapies. Digital pathology, particularly slide sharing for remote consultations, could cut days out of this process, providing a faster path to treatment.

This theme of reducing time-to-treatment was echoed by multiple panelists. Dr. Joseph Annunziata, a molecular pathologist and lab director, emphasized the importance of integrating DP to facilitate faster workflows, especially in community hospitals, where digital tools are often not yet in place. He also stressed the need for reflex testing panels, which allow pathologists to automatically order crucial molecular tests, such as next-generation sequencing (NGS), without needing separate oncologist input each time. This streamlining of diagnostic procedures, according to Annunziata, can significantly improve turnaround times, especially in cases requiring complex molecular profiling.

Omar Perez, PhD, from AstraZeneca’s medical diagnostics team, provided a perspective from the pharmaceutical industry, highlighting the role digital pathology plays in identifying patients for personalized treatments, such as companion diagnostics. He observed that digital pathology is not only a laboratory tool but is becoming integral in clinical decision-making, particularly for evaluating biomarkers that guide precision treatments. Perez made the compelling point that for advanced-stage cancers, where time is a critical factor, digital tools could be vital in expediting the analysis of biopsy results and molecular data, enabling oncologists to initiate appropriate therapies sooner.

The discussion touched on the barriers to adopting digital pathology more broadly, particularly in terms of infrastructure and cost. Dr. Gaulin and Dr. Annunziata noted that while larger academic institutions may have the necessary infrastructure, community hospitals and smaller institutions are often left out of the equation due to high costs and lack of IT integration. Gaulin emphasized that this divide needs to be addressed if the full potential of digital pathology is to be realized. Dr. Annunziata also pointed out that although digital tools can save days in consult times, their financial benefits might not always be immediately clear to administrators, which can slow adoption in cost-sensitive environments.

Perhaps one of the most enlightening aspects of the webinar was its emphasis on collaboration. Dr. Perez and the other panelists stressed that oncologists, pathologists, and pharmaceutical companies must collaborate more closely to standardize diagnostic tools, reduce fragmentation, and ensure patients have access to the best possible care. By integrating molecular tumor boards and embracing digital consultations, institutions can unify their decision-making processes, improving both the accuracy and speed of diagnosis.

In closing, the panelists emphasized that while digital pathology adoption has been slow, the evidence supporting its clinical and financial value is growing. With more studies on the horizon—particularly focusing on how digital tools can improve turnaround times and patient outcomes—the panel suggested that we may be at the cusp of a broader revolution in how oncology and pathology interact.

Here are ten key takeaways from the The Role of the Oncologist in the Digital Pathology Revolution webinar:

• 1. Expanding Role of Oncologists: Oncologists are becoming key stakeholders in digital pathology, particularly as tools shift from lab efficiencies to answering clinical questions.

• 2. Faster Consultations: Digital pathology can speed up the consultation process by enabling remote slide sharing, potentially shaving off several days from diagnostic delays.

• 3. Reflex Testing for Efficiency: Automatic reflex testing panels, particularly for molecular markers, streamline workflows, allowing pathologists to order critical tests upfront without waiting for oncologist input.

• 4. Predictive and Prognostic Tools: Digital pathology tools are increasingly linked to companion diagnostics and predictive algorithms, which can guide personalized cancer treatments.

• 5. Cross-Disciplinary Collaboration: Greater collaboration between pathologists, oncologists, and pharmaceutical companies is crucial for the successful implementation and utilization of digital pathology.

• 6. Centralized Tumor Boards: Digital tools enhance multidisciplinary tumor boards by allowing pathologists to participate remotely, sharing insights and contributing to faster treatment decisions.

• 7. Financial Barriers: The high costs of implementing digital pathology, especially for smaller or community hospitals, remain a significant barrier to widespread adoption.

• 8. Infrastructure Challenges: IT integration and the lack of unified systems across hospitals further slow the adoption of digital pathology tools.

• 9. Patient Impact: For patients with late-stage cancers, faster diagnostic turnaround times enabled by digital pathology could lead to quicker initiation of treatments and better outcomes.

• 10. Future Research: Ongoing studies are expected to provide more evidence on how digital pathology improves clinical outcomes, which may drive broader adoption in the coming years.

FDA and Why HLA Tests Won't Be Regulated Right Now

 AI discussion then original FDA text follows.

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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 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 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, and

·        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.

Scite.AI: MRD Studies in Lung Cancer

 There seem to be many fewer studies for Minimal Residual Disease monitoring (MRD) in lung cancer, compared to colorectal cancer. What are the best studies of MRD in lung cancer (circulating tumor DNA) and if possible discuss why this field lags behind MRD studies in colorectal cancer.

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SCITE.AI

Minimal Residual Disease (MRD) monitoring in lung cancer, particularly through the analysis of circulating tumor DNA (ctDNA), has garnered attention, yet it remains significantly less explored compared to colorectal cancer. This disparity can be attributed to several factors, including the complexity of lung cancer biology, the historical focus on colorectal cancer in MRD studies, and the challenges associated with ctDNA detection in lung cancer.

 Recent studies have begun to elucidate the potential of ctDNA in monitoring MRD in lung cancer. For instance, demonstrated that longitudinally undetectable MRD in localized non-small cell lung cancer (NSCLC) patients correlates with a high likelihood of remaining disease-free, suggesting a potential for identifying a "cured" population within this cohort (Zhang et al., 2022). Furthermore, highlighted the efficacy of ctDNA profiling in early detection of MRD, emphasizing its role in guiding treatment decisions (Chaudhuri et al., 2017). These findings indicate that while the prognostic value of ctDNA in lung cancer is promising, the body of research is still developing.

 In contrast, colorectal cancer has seen a more robust integration of ctDNA in MRD monitoring. Studies such as those by have established ctDNA as a reliable biomarker for recurrence in resected colorectal cancer, demonstrating its superiority over traditional imaging methods in certain contexts (Fakih et al., 2022). The comparative abundance of studies in colorectal cancer can be attributed to its well-defined treatment pathways and the established role of biomarkers like carcinoembryonic antigen (CEA) in clinical practice (Fakih et al., 2022). This has facilitated a more extensive exploration of ctDNA applications, leading to a wealth of data supporting its use in MRD monitoring.

 The lag in lung cancer research can also be linked to the inherent biological complexities of lung tumors. noted that most studies have focused on single qualitative markers in ctDNA, such as specific mutations (e.g., EGFR and KRAS), rather than adopting a comprehensive multi-marker approach that has proven effective in colorectal cancer (Szpechcinski et al., 2015). This limitation in study design may hinder the broader applicability of ctDNA as a reliable MRD marker in lung cancer.

 Moreover, the technical challenges associated with ctDNA detection in lung cancer cannot be overlooked. The sensitivity of ctDNA assays can be affected by the tumor's heterogeneity and the low levels of ctDNA present in the bloodstream, particularly in early-stage disease (Yan & Liu, 2022). This contrasts with colorectal cancer, where ctDNA levels are often higher and more consistent, facilitating easier detection and monitoring.

 In summary, while there are promising studies indicating the potential of ctDNA for MRD monitoring in lung cancer, the field lags behind colorectal cancer due to a combination of historical focus, biological complexity, and technical challenges in ctDNA detection. Continued research and the development of more sensitive and comprehensive ctDNA assays may bridge this gap in the future.

 ##

Could you focus on 2023 and 2024 studies of circulating tumor dna to detect minimal residual disease (MRD) or recurrence, in lung cancer.

##

In recent years, the application of circulating tumor DNA (ctDNA) for monitoring minimal residual disease (MRD) and recurrence in lung cancer has gained traction, with several notable studies emerging in 2023 and 2024. These studies highlight the potential of ctDNA as a non-invasive biomarker for assessing disease status post-treatment and guiding clinical decisions.

 One significant study by Kang et al. (2023) introduced a dynamic methylation-based analysis of cell-free DNA for postoperative monitoring in lung cancer patients. The study found that patients with low MRD scores were unlikely to experience relapse within four months, suggesting that such a methylation-based approach could personalize postoperative management and reduce unnecessary imaging (Kang et al., 2023). This finding underscores the utility of ctDNA in providing timely insights into patient status, potentially leading to more tailored treatment strategies.

 Another important contribution is from (Franzi, 2023), who conducted a meta-analysis on the role of liquid biopsy in non-small cell lung cancer (NSCLC). The authors noted that dynamic changes in ctDNA levels correlated with therapeutic responses, indicating that ctDNA could be effectively used for early detection of MRD and recurrence in early-stage lung cancer (Franzi, 2023). This study reinforces the idea that ctDNA monitoring can enhance the management of lung cancer by identifying patients at risk for relapse.

 O'Sullivan et al. (2023) further explored the challenges and future directions of MRD monitoring in radically treated NSCLC. They emphasized that the variant allele frequency (VAF) of ctDNA is prognostic, particularly in early-stage patients. Those with detectable ctDNA prior to resection exhibited a higher risk of recurrence compared to those without detectable ctDNA, highlighting the potential of ctDNA as a predictive tool in clinical practice (O’Sullivan et al., 2023). This study illustrates the critical role of ctDNA in stratifying patients based on their risk of relapse, which could inform follow-up and treatment decisions.

 Desai (2024) also contributed to this field by discussing the integration of ctDNA into clinical practice for managing EGFR-mutant NSCLC. The study highlighted ctDNA's role in risk stratification and treatment decision-making, particularly for patients undergoing curative-intent treatment (Desai, 2024). This aligns with the growing recognition of ctDNA as a valuable tool for monitoring MRD and guiding therapeutic interventions.

 Moreover, Morgensztern (2024) emphasized the expanding role of ctDNA in resectable NSCLC, suggesting that its detection could facilitate personalized treatment approaches. By identifying patients at high risk for relapse, clinicians may opt for more aggressive therapies, while those at low risk could avoid overtreatment (Morgensztern, 2024). This personalized approach is crucial in improving outcomes for lung cancer patients.

 In summary, the studies from 2023 and 2024 collectively demonstrate the promising role of ctDNA in detecting MRD and predicting recurrence in lung cancer. The ability to provide real-time insights into disease status and risk stratification positions ctDNA as a vital component of modern oncological practice, particularly in the management of NSCLC.

 References:

Chaudhuri, A., Chabon, J., Lovejoy, A., Newman, A., Stehr, H., Azad, T., … & Diehn, M. (2017). Early detection of molecular residual disease in localized lung cancer by circulating tumor dna profiling. Cancer Discovery, 7(12), 1394-1403. https://doi.org/10.1158/2159-8290.cd-17-0716

Desai, A. (2024). Ctdna for the evaluation and management of egfr-mutant non-small cell lung cancer. Cancers, 16(5), 940. https://doi.org/10.3390/cancers16050940

Fakih, M., Sandhu, J., Wang, C., Kim, J., Chen, Y., Lai, L., … & Kaiser, A. (2022). Evaluation of comparative surveillance strategies of circulating tumor dna, imaging, and carcinoembryonic antigen levels in patients with resected colorectal cancer. Jama Network Open, 5(3), e221093. https://doi.org/10.1001/jamanetworkopen.2022.1093

Franzi, S. (2023). Liquid biopsy in non-small cell lung cancer: a meta-analysis of state-of-the-art and future perspectives. Frontiers in Genetics, 14. https://doi.org/10.3389/fgene.2023.1254839

Kang, G., Lizaso, A., Beck, S., Lyskjær, I., Chervova, O., Li, B., … & Wang, J. (2023). Individualized dynamic methylation-based analysis of cell-free dna in postoperative monitoring of lung cancer. BMC Medicine, 21(1). https://doi.org/10.1186/s12916-023-02954-z

Morgensztern, D. (2024). The expanding role of circulating tumor dna in resectable non–small cell lung cancer. Cancer, 130(10), 1730-1732. https://doi.org/10.1002/cncr.35268

O’Sullivan, H., Feber, A., & Popat, S. (2023). Minimal residual disease monitoring in radically treated non-small cell lung cancer: challenges and future directions. Oncotargets and Therapy, Volume 16, 249-259. https://doi.org/10.2147/ott.s322242

Szpechcinski, A., Chorostowska‐Wynimko, J., Struniawski, R., Kupis, W., Rudziński, P., Langfort, R., … & Orłowski, T. (2015). Cell-free dna levels in plasma of patients with non-small-cell lung cancer and inflammatory lung disease. British Journal of Cancer, 113(3), 476-483. https://doi.org/10.1038/bjc.2015.225

Yan, X. and Liu, C. (2022). Clinical application and prospect of mrd evaluation in lung cancer based on ctdna level: a review. Tumori Journal, 109(4), 356-362. https://doi.org/10.1177/03008916221101927

Zhang, J., Liu, S., Gao, W., Liu, S., Yan, H., Ji, L., … & Wu, Y. (2022). Longitudinal undetectable molecular residual disease defines potentially cured population in localized non–small cell lung cancer. Cancer Discovery, 12(7), 1690-1701. https://doi.org/10.1158/2159-8290.cd-21-1486

Chat GPT: CLIA Verification vs Validation.

 You are an expert on CLIA and clinical laboratory Policy.  What is the difference between "Verification" and "validation" in this context.  I think that verification has to do with bring up a complex IVD FDA-approved test for use, while validation has to do with validating an inhouse lab developed test (LDT).  However, don't assume I have that correct.

###

You are on the right track with your understanding of verification and validation in the context of CLIA (Clinical Laboratory Improvement Amendments) and clinical laboratory policy, but let's clarify these terms in more detail.

Verification refers to the process of confirming that a laboratory can accurately perform a test according to the specifications provided by the manufacturer of an FDA-approved or cleared test (typically an in vitro diagnostic [IVD] device). When a lab brings an IVD test into use, they must verify that they can replicate the test’s performance characteristics (e.g., accuracy, precision, sensitivity) as specified in the product labeling. This step ensures that the test performs as expected in the laboratory's specific setting but does not involve altering the test methodology.

Validation, on the other hand, is a more comprehensive process used primarily for laboratory-developed tests (LDTs), which are not FDA-approved or cleared. Validation involves establishing the test’s performance characteristics from the ground up, as there are no manufacturer specifications to verify. This includes defining and confirming accuracy, precision, sensitivity, specificity, and other relevant performance characteristics for the test in question. The lab essentially proves that the test is reliable for its intended use.

In summary:

Verification: Performed for FDA-approved/cleared tests (IVDs) to ensure the lab can run the test properly.

Validation: Required for in-house LDTs, where the lab must fully establish the test's performance characteristics.

Let me know if you need more details on either process!

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Assume I am preparing to be hired for a lab director role, and I need to answer an oral question contrasting and comparing the two processes.   Provide a more detailed answer suitable for someone interviewing to be a lab director.

##

Verification and validation are critical processes under CLIA, but they differ in scope, purpose, and regulatory requirements. Let’s start by defining each process:

1. Verification is required when a laboratory implements an FDA-approved or cleared test—typically an in vitro diagnostic (IVD) device. Since the test has already undergone rigorous validation by the manufacturer as part of the FDA approval process, the lab is not required to perform a full validation. Instead, the lab must verify that it can perform the test within its own environment and achieve the same performance characteristics specified by the manufacturer. The key parameters verified include:

   • Accuracy: Does the test provide results that match known standards?
   • Precision: Is the test reproducible, with minimal variation between runs?
   • Reportable Range: Does the test accurately report values across the intended range?
   • Reference Range: Do results fall within the expected normal ranges for the patient population?

   The process typically involves running controls and samples to confirm that the lab’s staff, equipment, and environment can maintain the test’s intended performance. Verification is especially focused on ensuring consistent application of a pre-established test in a new setting.

2. Validation, by contrast, applies to laboratory-developed tests (LDTs) or modified FDA-approved tests. Since LDTs are not FDA-reviewed, the lab must take full responsibility for proving that the test performs as intended. This process is more involved and includes:

   • Establishing Performance Characteristics: The lab must generate data to support accuracy, precision, sensitivity, specificity, and analytical range. 
   • Unlike verification, which confirms performance against an existing standard, validation requires building the evidence to define those standards.
   • Risk Assessment: As part of validation, the lab also conducts a thorough risk analysis, considering factors such as potential cross-reactivity, matrix effects, and robustness in various operating conditions.
   • Clinical Utility: The lab must demonstrate that the test’s results provide meaningful clinical information that can be used for patient care decisions, ensuring the test is fit for its intended clinical purpose.

Key Differences:

• Scope: Verification focuses on confirming performance characteristics established by the manufacturer, while validation involves defining and establishing these characteristics for a new or modified test.
• Regulatory Requirements: For verification, the lab is bound to follow the FDA-approved test's guidelines. 
• For validation, the lab takes on the responsibility for all aspects of test performance, requiring a higher degree of scrutiny and documentation.
• Complexity: Verification is a more straightforward process with predefined benchmarks, while validation involves more extensive, data-driven analysis to ensure the test is fit for its intended use.

Key Similarities:

• Both processes are crucial for ensuring that any test used in the clinical laboratory meets the necessary quality standards under CLIA and applicable regulatory guidelines.
• Both require careful documentation and adherence to the lab’s quality management system, including the monitoring of ongoing performance through quality control (QC) measures.

In summary, while verification is generally limited to confirming that an FDA-cleared test works as expected in the lab’s environment, validation is a more comprehensive process used when developing new tests or significantly modifying existing ones. As a lab director, it's important to oversee both processes to ensure compliance, maintain high-quality patient care, and mitigate risks associated with testing."

---

This answer highlights your knowledge of both processes, while also demonstrating your leadership capabilities in maintaining quality and regulatory compliance in the lab.

Order of Bullets in van Shaik, CGP Value

Original blog:   https://www.discoveriesinhealthpolicy.com/2024/09/journal-club-broad-tech-assessments-of.html 

##

SIDEBAR: Why the Order?

 

1. Actionable Mutations Were Common, but Impact Was Unclear: I put this first because finding actionable mutations is the core promise of CGP. But if these findings don't consistently lead to better outcomes, then the whole premise of CGP becomes questionable. This felt like the most important point to address upfront.

2. Limited Diagnostic Impact: After actionable mutations, I wanted to highlight the diagnostic value of CGP. If it's not significantly improving or refining diagnoses, it calls into question whether CGP is doing enough to justify its use. So, I placed this right after the actionable mutations discussion.

3. Matched Treatments Had Inconsistent Results: This comes next because the idea behind CGP is to guide personalized treatment. If matched treatments are inconsistent across studies, it’s a major limitation. I felt that once we’ve talked about actionable mutations and diagnostic impact, discussing treatment outcomes naturally follows.

4. Clinical Utility Limited by Treatment Access: Even if CGP finds actionable mutations, if patients can’t access the treatments due to insurance or logistical issues, then the real-world utility is limited. This is a practical barrier that felt important to address early on, right after the more theoretical points about mutations and diagnostics.

5. No Randomized Controlled Trials (RCTs): I placed this high on the list because RCTs are considered the gold standard for proving efficacy. The absence of RCTs really weakens the conclusions about CGP’s clinical utility, so it seemed important to mention early.

6. Turnaround Time Variability: Turnaround time directly affects patient care, and if it’s inconsistent or too slow, CGP’s practical value in clinical settings diminishes. I thought this was an operational issue that needed to be addressed before moving on to more abstract concerns like study design.

7. Lack of Standardization in Outcomes: This is a big frustration because it makes it hard to compare results across studies. Without standardized outcomes, we can’t draw solid conclusions about CGP’s effectiveness, so it felt like a key limitation to highlight after the discussion on practical and clinical issues.

8. Difficulty in Assessing Long-Term Benefits: I wanted to emphasize that CGP’s potential long-term benefits, like hereditary findings, are often overlooked. This is a missed opportunity, and I thought it was important to mention before moving on to methodological and cost-related issues.

9. Observational Study Design Challenges: Since observational studies are the main source of data for CGP, their limitations have to be acknowledged. But I placed this a bit lower because it’s more of a methodological issue, which feels secondary to clinical outcomes and real-world utility.

10. Lack of Cost-Effectiveness Data: Cost-effectiveness is critical when deciding whether to implement a technology like CGP, but without strong data here, it’s hard to justify its use. I placed this lower because while it’s important, clinical and operational factors seemed more pressing.

11. Limited Empirical Evidence: There’s a lack of empirical evidence for some factors, like laboratory organization and scientific spillover. This is a significant gap, but I placed it lower because it’s not as immediately impactful as the clinical and financial concerns.

12. Need for Real-World Evidence and Comprehensive Assessments: Finally, I wanted to end with a forward-looking recommendation. The need for more real-world evidence and comprehensive assessments summarizes what’s missing and where future research should go. It felt like a natural conclusion after discussing all the limitations.

This order begins with the most pressing clinical findings and gradually moves toward methodological, operational, and future research concerns, creating a logical flow that prioritizes patient-centered utility before broader or systemic issues.

OPPS Comment Radiopharm Competitive Settings

 TOPIC: Payment for diagnostic radiopharmaceuticals.   

III.V.B.c. 89 Fed Reg 59213-9.

I support the separate billing of certain costly radiopharmaceuticals.  This supports the fact that OPPS is a prospective payment system sensitive to major levels (APCs for Radiology 1, 2, 3 etc).  This use of packaging plus levels is also found in DRGs as are MS-DRGs (w/MCC, etc).

CMS does not mention in this context incentives or perverse incentives regarding location of service.  Currently, diagnostic radiopharmaceuticals in Part B non-facility settings are paid separately (e.g. $600 scan, $2000 tracer).   This provides a current incentive to use these tracers only in part of the nuclear scan places of service, creating a segmented and therefore less competitive market.  By paying for costly tracers separately in both freestanding and facility outpatient settings, there will be a more level playing field and more potential for competition.

Thank you! Your comment has been submitted to Regulations.gov for review by the the Centers For Medicare & Medicaid Services.   Comment Tracking Number: m0s-l837-lcz4