MolDX: Molecular Testing for Solid Organ Allograft Rejection - Open Public Meeting - August 26, 2025 - JF Part A

Jo Gilbertson
Good afternoon, everyone, and welcome to Noridian's Open Public Meeting. My name is Jo Gilbertson, and I am one of the Medical Policy Specialists here at Noridian Healthcare Solutions. We will be presenting MolDX: Molecular Testing for Solid Organ Allograft Rejection LCD.

Before we begin, I'd like to make some of the following announcements. This meeting will be recorded. Recording and written transcript will be posted to our website following today's meeting. All lines are currently being muted and will remain muted throughout the meeting. Only those who registered to present will be allowed to comment on the proposed LCD today.

For our presenters, you are being allotted 10 minutes to make your comments. Your line will be open when it is your turn to speak. Make sure you are not on mute within your system or we will not be able to hear your comments. You should be prepared to begin your oral comments immediately when called upon and will hear the moderator's voice when one-minute remains. If you reach the end of your 10-minute time limit your line will be muted and we will move on to our closing steps. We have added closed captioning features in real time for today's call. Please speak clearly enough so that the system will be able to translate into captions for display. As I had mentioned, the recording and transcript will be posted to our website. By signing in today, you are given consent to the use of your recorded voice and your comments. Please be mindful of sharing any personal health information during your oral presentation.

In addition to comments that are made today, all comments should be submitted in writing. All written comments received will be reported in the response to comments article.

I will now be turning the meeting over to Dr. Rajadhyaksha.

Dr. Rajadhyaksha, you may begin.

Dr. Rajadhyaksha:
Thank you so much for coming to this Open Meeting. Next slide, please.

So, the Open Meeting today is a Molecular Testing for Solid Organ Allograft Rejection. Next slide please.

These are some of the definitions which I won't go through. Next slide please.

Next slide please.

Thank you.

So, a little summary on the policy. This Medicare contractor will provide limited coverage for molecular diagnostic tests used in the evaluation and management of patients who have undergone solid organ transplant. These tests can inform decision-making along with standard clinical assessments in the evaluation of organ injury for active rejection.

These tests may be ordered by qualified physicians or providers operating within their scope of practice considering the diagnosis of the rejection, helping to rule out or rule in this condition and when assessing the need for or results of a diagnostic biopsy.

They should be considered along with other clinical evaluations and results and may be particularly useful in patients with significant contraindications to invasive procedures.

Next slide, please.

Next slide, please.

Is it not working? Hello?

Krista Babbitt:
It's moving on my end.

Is it not moving for anyone else?

Dr. Rajadhyaksha:
No. Thank you. Now it finally moved.

The intended use of the test must be to inform clinical decision-making as per the following:

To assist in the evaluation of adequacy of immunosuppression or response to treatment, where a non-invasive or minimally invasive test can be used in lieu of tissue biopsy, or:

As a rule out test for active rejection and validated populations of patients with clinical suspicion of rejection with a non-invasive minimally invasive test to make a clinical decision regarding obtaining a biopsy, or:

For further evaluation of allograft status for the probability of allograft rejection after a physician assessed pre-test review of clinical and biological factors concerning for risk of rejection or:

To assess rejection status in patients that have received a biopsy, but the biopsy results are inconclusive, unexpected given the patient's clinical lab or laboratory presentation or limited by insufficient material or:

To assess for subclinical rejection of an allograft (that is surveillance testing), according to a clinically validated cadence (in peer-reviewed published evidence or established national consensus guidelines) utilizing the minimum number of test standpoints that have demonstrated clinical utility appropriate for the specific transplant type. Next slide, please.

Jo Gilbertson:
We are thinking that there is a delay.

Dr. Rajadhyaksha:
Yeah. Thank you.

At this time, the current evidence supports a maximum number of surveillance time points for evaluation in the first-year post transplantation as follows. Kidney (4), Heart (12), and Lung (12). After the first year, surveillance time points may continue at a decreased frequency of two per year.

Next slide, please.

Next slide, please.

Krista Babbitt:
It moved.

Dr. Rajadhyaksha:
Yes, but I'm gonna skip this.

Krista Babbitt:
Oh, thank you. Okay, okay, sorry.

Dr. Rajadhyaksha:
For a given patient encounter, only one molecular test for assessing allograft status may be performed. A test may include more than one assay.

However, multi-analyte and combination tests must demonstrate superiority and additive benefit when compared to respective single analytes or components. For minimally or non-invasive tests, the benefits to risk profile of the molecular test is considered by the ordering clinician to be more favorable than the benefit to risk profile of a tissue biopsy, or a tissue biopsy cannot be obtained when the test and biopsy provide similar information. For example, this may be the case if a biopsy is considered medically contraindicated in a patient.

Next slide please.

The test successfully completes a MolDX technical assessment, and a test and biopsy cannot be performed simultaneously.

However, in very high-risk patients with overt signs and symptoms of rejection, a molecular test and biopsy may be performed together and urgent situations only when the information derived from the test is complementary to the biopsy, established to meet clinical validity requirements outlined above for that information and demonstrated to improve outcomes in patients when performed along with biopsies. We expect these situations to be extremely rare.

Covered tests with analytic validity that is significantly below similar services may have coverage rescinded. Next slide, please.

Now, I would like to ask Robert Woodworth, Chief Scientific Officer of CareDx, who would like to make a comment. There is no presentation associated with this.

Thank you.

Robert Woodworth:
Thank you for the opportunity to speak today. I will be speaking on behalf of CareDx regarding this draft LCD.

We appreciate that this draft and comment period as a means to engage stakeholders, including laboratories like CareDx, as well as clinicians and transplant recipients. We are pleased to see the detailed criteria list in the draft LCD covering many of the validated uses of non-invasive molecular testing. We especially appreciate the focus on surveillance testing, recognizing the evolution of evidence in clinical practice.

I am speaking today because we are concerned with the removal of coverage for some testing and the proposed limits on surveillance testing. We will submit a detailed written comment outlining coverage changes that we recommend, including the following:

First, that we recommend the existing coverage be maintained for combination testing in the post-heart transplant surveillance setting. Specifically, this is the heart care test comprising two assays, AlloMap, which is assessment of recipient immune activity, and AlloSure, measurement of graft injury.

Heart care meets the LCD-defined requirement, it has demonstrated superiority and added a benefit when compared to either AlloMap or to cell-free DNA alone.

Second, we recommend that the limits for surveillance testing introduced in this draft be removed or at least modified if the final LCD to align with guidelines, publications, and clinical practice. I'll briefly expand on each of these points.

Our request to maintain existing coverage of combination testing with heart care in the post-heart transplant surveillance setting is based on publication of large multi-center data from the SHORE study. The biological rationale for heart care combination testing is that the two assays measure different aspects of rejection pathology.

The AlloMap gene expression profiling assay, which I'll refer to as AlloMap or GEP, measures immune system activity through expression of genes and recipient blood cells, while the donor derived cell-free DNA assays measure evidence of graft injury by quantifying the percentage of cell-free DNA in the blood that is from the transplanted organ.

The heart care test has demonstrated clinical superiority in surveillance for rejection, which is the primary clinical context for the molecular testing in heart transplant. In this surveillance setting, the main value of molecular testing is the ability to identify patients at a higher likelihood of rejection, within the overall low-risk population. This is accomplished through the specificity and positive likelihood ratio of a test. The heart care performance in these critical characteristics was validated and the clinical utility demonstrated in the SHORE study. This study was an exceptionally large prospective multi-center study in heart transplant with the first publication just this past year.

The data from this publication included over 2,000 patients and 161 episodes of acute cellular rejection paired with molecular testing. 161 rejections is a very large number in heart transplant studies, and from this, definitive conclusions were reached. In this study, heart care was validated through a statistically significant improvement in specificity, and clinically meaningful and statistically significant improvement in positive likelihood ratio for dual positive combination testing compared to either donor derived cell-free DNA or GEP alone. The positive likelihood ratio integrates both sensitivity and specificity, and this is the most important performance characteristic in the surveillance context. This study also demonstrated significant utility.

The addition of GEP testing to cell-free DNA testing resulted in a decrease in biopsies.

In the first two years post-transplant, the reflex biopsy rate, that is, an invasive biopsy performed in response to the result of the non-invasive testing. This reflex biopsy rate was 36% lower when a negative GEP accompanied a positive cell-free DNA than when a positive GEP accompanied a positive cell-free DNA. The use of GEP, in addition to cell-free DNA, enabled a large decrease in reflex biopsies while maintaining outcomes. The added clinical benefit of heart care combined testing is well supported by the large-scale SHORE study. The two molecular assays should continue to be covered individually, of course, and also covered if ordered as the heart care test in the same patient encounter. The large multi-center clinical utility evidence clearly demonstrates that eliminating coverage of combination testing will lead to unnecessary biopsies.

I will now turn to addressing surveillance frequency limits.

The introduction of this restriction in the draft LCD would be a step backwards for the ability of physicians to apply testing as needed in transplant patients across the risk spectrum.

New Medicare payment models aimed at increasing kidney transplants and the dramatic increase in organs procured via donation after cardiac death are increasing the use of organs at elevated risk.

Data from UNOS shows a significant increase in hospitalization for patients, a hospitalization for rejection in patients who receive these organs, increasing the need to closely monitor these patients' post-transplant.

Rejection surveillance in solid organ transplantation enables identification of subclinical rejection. That is earlier detection of rejection, so it can be treated before it is detected through clinical signs and symptoms and causes irreparable injury to the allograft.

Prior to the innovation of molecular testing, rejection surveillance monitoring was accomplished with surveillance biopsies.

To the extent the frequency limits are premised on the frequency of surveillance biopsies. That limitation is inconsistent with the benefit-to-risk profile of non-invasive testing.

Surveillance biopsies across all organs are invasive and come with well-documented complication rates.

Historic frequency of rejection surveillance were not driven just by rejection risk but balanced against the procedure risk. In the era of reliable non-invasive molecular surveillance, the procedure risks no longer need to temper the decision to perform surveillance.

Frequency limits for surveillance testing should be removed, as clinicians well understand the risks associated with each individual transplant recipient.

To the extent that any surveillance frequency limits are retained, they should be supported by either guidelines, professional society consensus, or published studies representing current clinical practice. The draft policy suggests the logic followed for determining surveillance frequencies for heart included the 2023 ISHLT guidelines. These guidelines state that lifelong follow-up is necessary to monitor for rejection. For an uneventful clinical course, follow-up should occur 13 times in the first-year post-transplant and every three to six months thereafter.

Many published U.S. Center protocols for non-invasive testing mirror these ISHLT recommendations. Therefore, it is appropriate that the limit on molecular surveillance be increased to at least quarterly beyond one year to match guidelines and clinical practice.

In lung transplant, the median survival is just over six years, the lowest by far among major organ transplants. These high-risk transplant patients are monitored closely for rejection in the first year and continue routinely thereafter.

The draft LCD references a specific clinical utility study as the basis for establishing 12 surveillance episodes in year one post-transplant. We recommend that if a limit is to be included, the subsequent years follow the same publication, which used quarterly testing beyond year one.

The American Society of Transplant Surgeons recommendation on the frequency of surveillance testing in kidney transplant recipients recognizes that obtaining data from a prospective trial to define frequency may prove impractical and that evidence for clinical utility of donor-derived cell-free surveillance testing is clear. The ASTS suggests the most robust clinical data in surveillance testing was based on monthly intervals through month four and then quarterly starting month six.

This schedule was based on the KDIGO recommended testing frequencies for other non-invasive post-transplant tests and focused the most frequent testing at the time of highest immunological risk.

The addition of donor-derived cell-free DNA to this regimen empowers clinicians by providing them with an accurate, sensitive, and non-invasive biomarker of allograft injury that facilitates subclinical identification of rejection before functional impact occurs. This frequency is ultimately seven times in the first year and quarterly thereafter. Donor-derived cell-free DNA is the only non-invasive tool that can identify subclinical rejection. Studies have demonstrated that donor-derived cell-free DNA levels can be elevated months before biopsy confirmation of rejection, allowing clinicians to identify these patients in advance of clinical signs or symptoms of rejection and before irreversible damage to the allograft.

The frequency limits persist in the LCD, they should be increased to reflect the increasing risk profiles of transplant patients, follow professional society guidelines and recommendations, align with published studies and correct clinical practice, and reflect the more favorable benefit-to-risk profile of non-invasive testing compared to historic surveillance biopsy practices.

Transplantation is a unique medical situation, a definitive cure for end-stage organ failure that requires lifelong immunosuppression and close monitoring. Well-managed transplant recipients have exceptional lives and have benefited from non-invasive molecular testing for rejection that has become the new standard of care in transplantation.

We appreciate this policy's confirmation of surveillance testing. I look forward to your attention to our concerns in the final policy.

Thank you for your time and for the attention.

Dr. Rajadhyaksha:
Thank you for your comments. We look forward to getting your comments in writing. I would go on to the next slide and ask Jo Gilbertson to go over the next steps. Thank you.

Jo Gilbertson:
Thank you, Dr. Rajadhyaksha.

I can now communicate the next steps in the policy development process.

The comment period for the proposed LCD will remain open until August 31st, 2025.

All comments to be considered by our medical directors for the proposed LCD must be submitted in writing. Written comments can be emailed to policydraft@noridian.com or mailed to the address on your screen. Comment information for our proposed LCD is located on our website at noridianmedicare.com

Upon review of the comments, our medical directors will either finalize or retire the proposed LCD. Responses to comments will be reviewable in the response to comments article.

Please monitor our website or register for listserv notifications to be informed of actions taken on our proposed LCD. Dr. Rajadhyaksha, do you have anything else you would like to say before we end this meeting?

Dr. Rajadhyaksha:
No, thank you.

Good afternoon and thank you for joining.