Continuing patient access to innovative treatment options
Continuing patient access to innovative treatment options
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and moldx.policy@palmettogba.com with your message
Send Your Letter
Submit your written public comments via your email
Submit your letterAlternatively, you can manually send an email to policydraft@noridian.com and moldx.policy@palmettogba.com with your message.
What is going on?
On August 10, 2023, MolDX issued a call for public comment on proposed changes to Medicare coverage policy (the local coverage determination (LCD)) which provides coverage guidance for the use of molecular testing (including donor-derived cell-free DNA and gene expression profiling) in solid organ transplant recipients. The purported rationale for the revisions is to provide clarity of coverage criteria without “change in coverage from the current Policy”; however, a close reading of the revisions suggests the new policy would have substantive coverage implications along three important axes:
1. Frequency of Molecular Surveillance Testing Limited by Biopsy Protocol
2. Concurrent Molecular Testing and Biopsy
3. Multimodality Molecular Testing
Below, we review each in detail and describe how the new LCD may adversely impact clinical practice and patient care.
What is going on?
On August 10, 2023, MolDX issued a call for public comment on proposed changes to Medicare coverage policy (the local coverage determination (LCD)) which provides coverage guidance for the use of molecular testing (including donor-derived cell-free DNA and gene expression profiling) in solid organ transplant recipients. The purported rationale for the revisions is to provide clarity of coverage criteria without “change in coverage from the current Policy”; however, a close reading of the revisions suggests the new policy would have substantive coverage implications along three important axes:
1. Frequency of Molecular Surveillance Testing Limited by Biopsy Protocol
2. Concurrent Molecular Testing and Biopsy
3. Multimodality Molecular Testing
Below, we review each in detail and describe how the new LCD may adversely impact clinical practice and patient care.
Frequency of Molecular Surveillance Testing Limited by Biopsy Protocol
In the context of kidney transplantation, the primary purpose of a surveillance (or protocol) biopsy is to detect subclinical rejection (SCR), defined as rejection in the absence of overt clinical symptoms or laboratory abnormalities. Although more broadly utilized in the recent past, the role of routine surveillance biopsies in the era of modern immunosuppression has come into question [1, 2]. In a survey of US transplant programs in 2017, only a minority (38%) reported performing any kind of surveillance biopsies, with few (17%) doing so in a universal, non-risk stratified fashion [3]. Not surprisingly, the most current KDIGO guidelines on the management of kidney transplant recipients (2009) do not make a recommendation regarding surveillance biopsies, instead concluding that additional studies were needed to define populations in which the benefits of this practice exceeded its harms [4]. Despite this, however, the same guidelines make a recommendation for treating SCR, recognizing its association with eGFR decline, chronic graft injury, and graft loss, along with evidence that treatment can ameliorate the risk of these adverse outcomes [4-9]. This results in somewhat conflicting guidance, wherein treatment of SCR is advised, but none of the modalities endorsed for monitoring graft function (urine volume, urine protein excretion, or serum creatinine) are useful for its detection.
Molecular testing with donor-derived cell-free DNA (dd-cfDNA) provides an ideal solution to this conundrum. Several studies have demonstrated a strong correlation between dd-cfDNA and histologic rejection identified on surveillance biopsies, establishing a non-invasive alternative for detection of clinically actionable SCR [10, 11]. Furthermore, the superior correlation between dd cfDNA and molecular histology opens the door to detection of SCR that may not be apparent by traditional histology [11].
The proposed LCD tethers the ability to perform reimbursable surveillance testing with dd-cfDNA to an established surveillance biopsy protocol, essentially conflating the risk/benefit calculations for a non-invasive blood test with a resource-intensive interventional procedure that is neither guideline-endorsed nor broadly utilized in clinical practice [3, 4]. Furthermore, for centers without existing surveillance biopsy protocols, the proposed revisions to the LCD would restrict access to the only currently available strategy for non-invasive detection of subclinical rejection, precluding its recognition and treatment. Instead, the frequency of molecular surveillance testing should be left to the discretion and of the treating provider, allowing them to base this decision on the immunologic risk of their patient population and their clinical judgement regarding the time points post-transplant at which such surveillance would be most warranted.
Frequency of Molecular Surveillance Testing Limited by Biopsy Protocol
In the context of kidney transplantation, the primary purpose of a surveillance (or protocol) biopsy is to detect subclinical rejection (SCR), defined as rejection in the absence of overt clinical symptoms or laboratory abnormalities. Although more broadly utilized in the recent past, the role of routine surveillance biopsies in the era of modern immunosuppression has come into question [1, 2]. In a survey of US transplant programs in 2017, only a minority (38%) reported performing any kind of surveillance biopsies, with few (17%) doing so in a universal, non-risk stratified fashion [3]. Not surprisingly, the most current KDIGO guidelines on the management of kidney transplant recipients (2009) do not make a recommendation regarding surveillance biopsies, instead concluding that additional studies were needed to define populations in which the benefits of this practice exceeded its harms [4]. Despite this, however, the same guidelines make a recommendation for treating SCR, recognizing its association with eGFR decline, chronic graft injury, and graft loss, along with evidence that treatment can ameliorate the risk of these adverse outcomes [4-9]. This results in somewhat conflicting guidance, wherein treatment of SCR is advised, but none of the modalities endorsed for monitoring graft function (urine volume, urine protein excretion, or serum creatinine) are useful for its detection.
Molecular testing with donor-derived cell-free DNA (dd-cfDNA) provides an ideal solution to this conundrum. Several studies have demonstrated a strong correlation between dd-cfDNA and histologic rejection identified on surveillance biopsies, establishing a non-invasive alternative for detection of clinically actionable SCR [10, 11]. Furthermore, the superior correlation between dd cfDNA and molecular histology opens the door to detection of SCR that may not be apparent by traditional histology [11].
The proposed LCD tethers the ability to perform reimbursable surveillance testing with dd-cfDNA to an established surveillance biopsy protocol, essentially conflating the risk/benefit calculations for a non-invasive blood test with a resource-intensive interventional procedure that is neither guideline-endorsed nor broadly utilized in clinical practice [3, 4]. Furthermore, for centers without existing surveillance biopsy protocols, the proposed revisions to the LCD would restrict access to the only currently available strategy for non-invasive detection of subclinical rejection, precluding its recognition and treatment. Instead, the frequency of molecular surveillance testing should be left to the discretion and of the treating provider, allowing them to base this decision on the immunologic risk of their patient population and their clinical judgement regarding the time points post-transplant at which such surveillance would be most warranted.
Concurrent Molecular Testing and Biopsy
Although frequently used in for-cause settings to help guide the decision to pursue biopsy, dd-cfDNA has also been studied and utilized in a variety of other clinical contexts, including those where histologic assessment was recently performed or being planned. Specifically, levels of dd-cfDNA obtained concurrently with biopsies demonstrating borderline T-cell mediated rejection (BL-TCMR) or TCMR1A have shown prognostic utility with respect to risk of eGFR decline, dnDSA detection, and recurrent rejection [12]. In another study, biopsy-paired dd-cfDNA results improved the performance of histology-based predictive models of graft function [13]. Concurrent testing can also help establish a tighter cross-sectional correlation between histologic findings and dd-cfDNA results. At centers where response to therapy is assessed using dd-cfDNA (in lieu of biopsy), having a dd-cfDNA result temporally close to the rejection event and before the start of treatment can better help evaluate the adequacy of response and preclude the need for follow-up histologic assessment [11].
The proposed LCD revisions cite settings where biopsy was either recently performed or already planned as examples where molecular diagnostics would not inform clinical decision making, however, as the cited studies demonstrate, information from concurrent molecular & histologic testing can help clinicians make decisions about immunosuppression management, long-term prognostication, and need for or timing of repeat biopsies. Rather than instituting a blanket policy on concurrent testing, clinicians should be given the flexibility to determine when simultaneous histologic and molecular assessment may help them make these decisions.
Concurrent Molecular Testing and Biopsy
Although frequently used in for-cause settings to help guide the decision to pursue biopsy, dd-cfDNA has also been studied and utilized in a variety of other clinical contexts, including those where histologic assessment was recently performed or being planned. Specifically, levels of dd-cfDNA obtained concurrently with biopsies demonstrating borderline T-cell mediated rejection (BL-TCMR) or TCMR1A have shown prognostic utility with respect to risk of eGFR decline, dnDSA detection, and recurrent rejection [12]. In another study, biopsy-paired dd-cfDNA results improved the performance of histology-based predictive models of graft function [13]. Concurrent testing can also help establish a tighter cross-sectional correlation between histologic findings and dd-cfDNA results. At centers where response to therapy is assessed using dd-cfDNA (in lieu of biopsy), having a dd-cfDNA result temporally close to the rejection event and before the start of treatment can better help evaluate the adequacy of response and preclude the need for follow-up histologic assessment [11].
The proposed LCD revisions cite settings where biopsy was either recently performed or already planned as examples where molecular diagnostics would not inform clinical decision making, however, as the cited studies demonstrate, information from concurrent molecular & histologic testing can help clinicians make decisions about immunosuppression management, long-term prognostication, and need for or timing of repeat biopsies. Rather than instituting a blanket policy on concurrent testing, clinicians should be given the flexibility to determine when simultaneous histologic and molecular assessment may help them make these decisions.
Multi-modality Molecular Testing
Definitive diagnosis and characterization of disease states frequently requires comprehensive and multimodal laboratory investigation. For example, guideline-based assessment of anemia in chronic kidney disease requires a complete blood count (CBC), absolute reticulocyte count, serum ferritin level, serum transferring saturation (TSAT), as well as vitamin B12 and folate levels [14]. Each analyte provides distinct and non-interchangeable information that can help characterize the etiology of anemia. In the case of iron deficiency anemia, a combination of findings (low mean corpuscular volume (MCV), low TSAT, and low ferritin) provides much more diagnostic certainty about the underlying diagnosis than any of the abnormalities in isolation. Multimodal assessment utilizing dd cfDNA and gene expression profiling (GEP) in solid organ transplantation offer similar clinical utility, providing information on distinct biologic processes (graft injury vs recipient immune activation). The results from paired testing demonstrate better diagnostic performance for active rejection than either assay alone, improving confidence for clinician decision-making, including whether invasive assessment with biopsy is warranted or can be safely avoided [15, 16].
The proposed LCD makes a point of emphasizing that various molecular tests have “…different strengths and weaknesses,” acknowledging for instance that “…some GEP tests have high negative predictive value for the likelihood of AR, but may be limited in their ability as a positive predictor for ACR or even detecting AMR.” However, rather than recognizing the potential value in pairing molecular tests that can yield complementary information, the LCD instead aims to restrict such use, a limitation that will increase the rate of false positives and negatives even when test selection is optimally tailored to the immunologic risk of the population. Clinicians utilizing molecular assays at transplant centers across the country have developed a good understanding of their utility in various clinical contexts, including those where multimodality testing may provide invaluable complementary information. Deferring to their expertise in determining when this might be appropriate reflects a more patient-centric approach to policy.
Multi-modality Molecular Testing
Definitive diagnosis and characterization of disease states frequently requires comprehensive and multimodal laboratory investigation. For example, guideline-based assessment of anemia in chronic kidney disease requires a complete blood count (CBC), absolute reticulocyte count, serum ferritin level, serum transferring saturation (TSAT), as well as vitamin B12 and folate levels [14]. Each analyte provides distinct and non-interchangeable information that can help characterize the etiology of anemia. In the case of iron deficiency anemia, a combination of findings (low mean corpuscular volume (MCV), low TSAT, and low ferritin) provides much more diagnostic certainty about the underlying diagnosis than any of the abnormalities in isolation. Multimodal assessment utilizing dd cfDNA and gene expression profiling (GEP) in solid organ transplantation offer similar clinical utility, providing information on distinct biologic processes (graft injury vs recipient immune activation). The results from paired testing demonstrate better diagnostic performance for active rejection than either assay alone, improving confidence for clinician decision-making, including whether invasive assessment with biopsy is warranted or can be safely avoided [15, 16].
The proposed LCD makes a point of emphasizing that various molecular tests have “…different strengths and weaknesses,” acknowledging for instance that “…some GEP tests have high negative predictive value for the likelihood of AR, but may be limited in their ability as a positive predictor for ACR or even detecting AMR.” However, rather than recognizing the potential value in pairing molecular tests that can yield complementary information, the LCD instead aims to restrict such use, a limitation that will increase the rate of false positives and negatives even when test selection is optimally tailored to the immunologic risk of the population. Clinicians utilizing molecular assays at transplant centers across the country have developed a good understanding of their utility in various clinical contexts, including those where multimodality testing may provide invaluable complementary information. Deferring to their expertise in determining when this might be appropriate reflects a more patient-centric approach to policy.
Alternatively, you can manually send an email to policydraft@noridian.com and moldx.policy@palmettogba.com with your message
References
1. Wilkinson A. Protocol transplant biopsies: are they really needed? Clin J Am Soc Nephrol. 2006;1(1):130-7.
2. Rush D, Arlen D, Boucher A, Busque S, Cockfield SM, Girardin C, et al. Lack of benefit of early protocol biopsies in renal transplant patients receiving TAC and MMF: a randomized study. Am J Transplant. 2007;7(11):2538-45.
3. Mehta R, Cherikh W, Sood P, Hariharan S. Kidney allograft surveillance biopsy practices across US transplant centers: A UNOS survey. Clin Transplant. 2017;31(5).
4. Kidney Disease: Improving Global Outcomes Transplant Work G. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009;9 Suppl 3:S1-155.
5. Seifert ME, Agarwal G, Bernard M, Kasik E, Raza SS, Fatima H, et al. Impact of Subclinical Borderline Inflammation on Kidney Transplant Outcomes. Transplant Direct. 2021;7(2):e663.
6. Mehta RB, Tandukar S, Jorgensen D, Randhawa P, Sood P, Puttarajappa C, et al. Early subclinical tubulitis and interstitial inflammation in kidney transplantation have adverse clinical implications. Kidney International. 2020;98(2):436-47.
7. Rush D, Nickerson P, Gough J, McKenna R, Grimm P, Cheang M, et al. Beneficial effects of treatment of early subclinical rejection: a randomized study. Journal of the American Society of Nephrology. 1998;9(11):2129-34.
8. Nankivell BJ, Chapman JR. The significance of subclinical rejection and the value of protocol biopsies. Am J Transplant. 2006;6(9):2006-12.
9. Kee TY, Chapman JR, O'Connell PJ, Fung CL, Allen RD, Kable K, et al. Treatment of subclinical rejection diagnosed by protocol biopsy of kidney transplants. Transplantation. 2006;82(1):36-42.
10. Bu L, Gupta G, Pai A, Anand S, Stites E, Moinuddin I, et al. Validation and clinical outcome in assessing donor-derived cell-free DNA monitoring insights of kidney allografts with longitudinal surveillance (ADMIRAL) study. Kidney Int. 2021.
11. Gupta G, Moinuddin I, Kamal L, King AL, Winstead R, Demehin M, et al. Correlation of Donor-derived Cell-free DNA With Histology and Molecular Diagnoses of Kidney Transplant Biopsies. Transplantation. 2022;106(5):1061-70.
12. Stites E, Kumar D, Olaitan O, John Swanson S, Leca N, Weir M, et al. High levels of dd-cfDNA identify patients with TCMR 1A and borderline allograft rejection at elevated risk of graft injury. Am J Transplant. 2020.
13. Huang E, Gillespie M, Ammerman N, Vo A, Lim K, Peng A, et al. Donor-derived Cell-free DNA Combined With Histology Improves Prediction of Estimated Glomerular Filtration Rate Over Time in Kidney Transplant Recipients Compared With Histology Alone. Transplantation Direct. 2020;6(8):e580.
14. Chapter 1: Diagnosis and evaluation of anemia in CKD. Kidney Int Suppl (2011). 2012;2(4):288-91.
15. Akalin E, Weir MR, Bunnapradist S, Brennan DC, Delos Santos R, Langone A, et al. Clinical Validation of an Immune Quiescence Gene Expression Signature in Kidney Transplantation. Kidney360. 2021.
16. Park S, Guo K, Heilman RL, Poggio ED, Taber DJ, Marsh CL, et al. Combining Blood Gene Expression and Cellfree DNA to Diagnose Subclinical Rejection in Kidney Transplant Recipients. Clin J Am Soc Nephrol. 2021;16(10):1539-51.
References
1. Wilkinson A. Protocol transplant biopsies: are they really needed? Clin J Am Soc Nephrol. 2006;1(1):130-7.
2. Rush D, Arlen D, Boucher A, Busque S, Cockfield SM, Girardin C, et al. Lack of benefit of early protocol biopsies in renal transplant patients receiving TAC and MMF: a randomized study. Am J Transplant. 2007;7(11):2538-45.
3. Mehta R, Cherikh W, Sood P, Hariharan S. Kidney allograft surveillance biopsy practices across US transplant centers: A UNOS survey. Clin Transplant. 2017;31(5).
4. Kidney Disease: Improving Global Outcomes Transplant Work G. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009;9 Suppl 3:S1-155.
5. Seifert ME, Agarwal G, Bernard M, Kasik E, Raza SS, Fatima H, et al. Impact of Subclinical Borderline Inflammation on Kidney Transplant Outcomes. Transplant Direct. 2021;7(2):e663.
6. Mehta RB, Tandukar S, Jorgensen D, Randhawa P, Sood P, Puttarajappa C, et al. Early subclinical tubulitis and interstitial inflammation in kidney transplantation have adverse clinical implications. Kidney International. 2020;98(2):436-47.
7. Rush D, Nickerson P, Gough J, McKenna R, Grimm P, Cheang M, et al. Beneficial effects of treatment of early subclinical rejection: a randomized study. Journal of the American Society of Nephrology. 1998;9(11):2129-34.
8. Nankivell BJ, Chapman JR. The significance of subclinical rejection and the value of protocol biopsies. Am J Transplant. 2006;6(9):2006-12.
9. Kee TY, Chapman JR, O'Connell PJ, Fung CL, Allen RD, Kable K, et al. Treatment of subclinical rejection diagnosed by protocol biopsy of kidney transplants. Transplantation. 2006;82(1):36-42.
10. Bu L, Gupta G, Pai A, Anand S, Stites E, Moinuddin I, et al. Validation and clinical outcome in assessing donor-derived cell-free DNA monitoring insights of kidney allografts with longitudinal surveillance (ADMIRAL) study. Kidney Int. 2021.
11. Gupta G, Moinuddin I, Kamal L, King AL, Winstead R, Demehin M, et al. Correlation of Donor-derived Cell-free DNA With Histology and Molecular Diagnoses of Kidney Transplant Biopsies. Transplantation. 2022;106(5):1061-70.
12. Stites E, Kumar D, Olaitan O, John Swanson S, Leca N, Weir M, et al. High levels of dd-cfDNA identify patients with TCMR 1A and borderline allograft rejection at elevated risk of graft injury. Am J Transplant. 2020.
13. Huang E, Gillespie M, Ammerman N, Vo A, Lim K, Peng A, et al. Donor-derived Cell-free DNA Combined With Histology Improves Prediction of Estimated Glomerular Filtration Rate Over Time in Kidney Transplant Recipients Compared With Histology Alone. Transplantation Direct. 2020;6(8):e580.
14. Chapter 1: Diagnosis and evaluation of anemia in CKD. Kidney Int Suppl (2011). 2012;2(4):288-91.
15. Akalin E, Weir MR, Bunnapradist S, Brennan DC, Delos Santos R, Langone A, et al. Clinical Validation of an Immune Quiescence Gene Expression Signature in Kidney Transplantation. Kidney360. 2021.
16. Park S, Guo K, Heilman RL, Poggio ED, Taber DJ, Marsh CL, et al. Combining Blood Gene Expression and Cellfree DNA to Diagnose Subclinical Rejection in Kidney Transplant Recipients. Clin J Am Soc Nephrol. 2021;16(10):1539-51.