1 Proposal to Establish a National Liver Review BoardLiver and Intestinal Organ Transplantation Committee Hello, my name is _______ and I will be presenting the Liver Committee’s proposal to Establish a National Liver Review Board

2 NLRB Timeline OPTN Board June 2017 or Dec 2017 Spring 2016 Fall 2016Structure of NLRB -broad support Fall 2016 Adult Guidance Changes to standard HCC policy to reflect current practice -2 of 3 proposed components supported and passed by Board Spring 2017 Structure of NLRB- minor revisions Adult Guidance- minor revisions Pediatric and HCC Guidance Fixed Exception score proposal NLRB Timeline OPTN Board June 2017 or Dec 2017 The NLRB project includes several efforts by the Committee over the last year. In Spring 2016, the Committee put forth a proposal that included the structure of the NLRB. It was greeted with broad support by the regions. In Fall 2016, the Committee put forth the a guidance document for review board members to used for Adult diagnoses falling outside of standardized criteria and changes to standardized criteria for HCC exceptions. The guidance document received broad support during the regional meetings and the HCC Proposal was eventually approved by the Board of Directors in December with 2 of the 3 proposed components. The current proposals include minor revisions to the structure of the NLRB and Adult guidance document, and the introduction of a fixed exception score, as well as Pediatric and HCC guidance documents for the NLRB.

3 Scope of NLRB Project Policy Guidance documentsStructure & operations of NLRB already supported in public comment Winter New proposed policy change only relates to the appeals process (“ART”= appeals review team). New proposed policy changes: fixed points assignment for candidates meeting standardized MELD/PELD exception criteria (versus current escalator) Guidance documents Adult MELD Exception Guidance Document: already supported in August public comment. Currently, minor proposed revisions to language. NEW Pediatric MELD/PELD Exception Guidance Document NEW HCC (non-standardized exception) Guidance Document The NLRB project is quite large, and we have 2 public comment proposals to discuss with you today. There is a policy proposal that you have seen before that establishes the NLRB. The revision to that is the organization of the appeals process. The new component is a proposal which changes modifies the way in which points are assigned to candidates meeting standardized exceptions in policy. In addition, there is a proposal to create 3 guidance documents which are meant to help guide centers and the review boards. You have seen the adult guidance document previously and this has been revised slightly as a result of the fall public comment. In addition, a new guidance document has been created for pediatrics and one for non-standard HCC cases.

4 2nd Appeal (Conference call)What’s new in 2017 proposal NLRB Structure 2016 2017 Structure 3 specialty boards (Adult, HCC, Pediatrics) No Change 1st Appeal (written) Different reviewers for first appeal Same reviewers as initial application 2nd Appeal (Conference call) Teleconference with reviewers of 1st appeal Appeal Review Team (ART) Override Kept override button Remove override button The current proposal only differs slightly from what went out for public comment in January There have been minor changes made to the appeals process, notably a change to the type of reviewer assigned to appeals and the introduction of the Appeal Review Team or ART, and the removal of the override button from policy. These changes are detailed in subsequent slides.

5 What’s new in 2017 proposal NLRB Points Points 2016 2017 Not discussed“Fixed Floor” score. MELD Elevator is removed and score fixed based on Median MELD at Transplant The 2016 proposal sought feedback from the community regarding the score for exception candidates and did propose a change. The current proposal changes the system and policy regarding points for exception candidates. These changes will be detailed in subsequent slides.

6 What’s new in 2017 proposal NLRB Guidance 2016 2017 AdultWent out for PC in Fall 2016 Inclusion of pre-existing NET, PLD, PSC and POPH. Minor changes to Budd Chiari and Hepatic Adenoma exception Pediatric In development New HCC The Board previously approved guidance for four standardized exceptions: Neuroendocrine Tumors (NET); Polycystic Liver Disease (PLD); Primary Sclerosing Cholangitis (PSC); and Portopulmonary Hypertension. Because this guidance was approved in June 2015, the Committee did not include those sections in the proposed guidance in the August 2016 version. This version of the proposal includes the guidance previously approved now combined into one document. The Committee also proposes clerical and grammatical changes to the existing PLD section to make it more understandable. Finally, there were minor changes made to the recommendation for Budd Chiari and hepatic adenoma exception. These will be detailed in subsequent slides. The Pediatric and non-standard HCC guidance documents were in development in 2016 and are new to the community. These will be explained in detail in subsequent slides.

7 What problems will the proposal solve?Regional agreements lead to variation in MELD exception score assignments Inefficiencies that lead to delays in awarding exception points Possible contribution of current MELD exception policy of scores increasing by fixed steps every three months to the escalation of median MELD score at transplant across every region (reference on next slide ) Currently, each region has adopted independent criteria they use to request and approve exceptions for liver candidates with specific diagnoses. Referred to as “regional agreements,” some believe these agreements may contribute to regional differences in exception submission and award practices, even among regions with similar transplant demographics. The current system also has inefficiencies that lead to delays in candidates being awarded exception points, and create excess work for review board chairs, who already review over 1,000 standardized exception requests each year. Determination of the optimal method of awarding exception scores for a national review board is challenging, given there are differences in median MELD score across the regions. The MELD exception score for many standardized exception diagnoses begins at 22 points and automatically increases every three months if the candidate continues to meet policy criteria. This automatic 10% score increase every three-months is referred to as the “MELD elevator.” This system is problematic because the transplant rate and the waitlist mortality for non-exception candidates is significantly higher in many region than for exception candidates. Non-standard exceptions are often awarded similar scores as standard exception patients. Some suggest that the MELD elevator has contributed to MELD inflation, the escalation in MELD score at transplant that has occurred over the past decade.

8 What problems will the proposal solve?MELD “Inflation”: Northrup et al Hepatology 2015 Death on waitlist 4.5% with exceptions versus 24.6% without exceptions. Transplant rate 79% with exceptions, vs 40% without This slide with data from Northrup et al details this concept of MELD “inflation” further. It was shown that non-exception candidates encounter a higher rate of waitlist mortality and a lower rate of transplant.

9 What are the proposed solutions?NLRB is comprised of 3 specialty review boards Adult HCC Adult Other Diagnosis Pediatrics Representation Every liver transplant program may appoint a representative Rep. Responsibilities Reps must vote within 7 days on all exception requests Non-responsiveness may result in suspension of program’s participation in NLRB As I mentioned, the structure of the NLRB was previously distributed for public comment in January 2016, and the proposed structure remains largely similar to the previous proposal. The NLRB is comprised of specialty boards, including: • Adult Hepatocellular Carcinoma (HCC) (for those candidates with HCC that do not meet the standardized criteria in policy) • Adult Other Diagnosis • Pediatrics, which reviews requests made on behalf of any candidate registered before they turn 18 and adults with certain pediatric diagnoses Every active liver transplant program may appoint a representative and alternate to each of the adult specialty boards. A liver transplant program with an active pediatric component may appoint a representative and alternate to the pediatric specialty board. Individuals may serve on more than one specialty board at the same time. Liver transplant programs are not required to provide a representative to the NLRB. Representatives must vote within 7 days on all exception requests, exception extension requests, and appeals. If a representative or alternate does not vote on an open request within 7 days on three separate instances within a 12 month period, the Chair will remove the individual from the NLRB. If a transplant program exhibits a pattern of non-responsiveness, as evidenced by the removal of two members from the NLRB, the Chair may suspend the program’s participation for a period of three months after notifying the program director.

10 What are the proposed solutions?Voting Exception request is randomly assigned to five reps of the appropriate board Appeal Process The same five reps of the original request review the appeal ART (Modification from January 2016 proposal) If appeal is denied, a conference call may be requested with the Appeals Review Team (ART) All NLRB members are assigned to serve one month each year on the ART (9 member teams, require 5 for quorum). Conference calls will be held at a fixed day each week and cancelled only if there are no cases Following ART denial, program may initiate final appeal to the Liver Committee Voting Procedure An exception request is randomly assigned to five representatives of the appropriate specialty board. A representative may vote to approve or deny the request, or ask that the request be reassigned. A liver program may appeal the NLRB’s decision to deny an exception request. The same five members that reviewed the original request will review the appeal. This is one of the changes we made since the previous round of public comment: we think the same 5 reviewers should review the appeal (instead of a new group of 5) because they’ll be more familiar with the case and the supplemental information the appealing program will submit. It also cuts down on workload for other review board members. If the appeal is denied, the liver program may request a conference call with the Appeals Review Team (ART). If the ART denies the request, the liver program may initiate a final appeal to the Liver and Intestinal Organ Transplantation Committee. The ART was created after the previous round of public comment. At the beginning of each new service term, members of the NLRB are assigned to serve 1 month on the ART. The ART will meet via conference call at the same day and time each week. Nine ART members will be assigned to each call and 5 will be required for quorum. Calls may be rescheduled in advance to accommodate federal holidays. The ART will operate more efficiently than the current practice of trying to schedule teleconferences for appeals, because their schedules will be set far in advance. Notably, the Committee proposes eliminating the ability to override the decision of the NLRB. Since the override was implemented on February 4, 2016, only one transplant program has ever used it. The Committee believes its limited use, plus the ability to register a candidate as status 1A, negates the need for the override.

11 What are the proposed solutions?Cap on Exception Points Adult standard exceptions: if the candidate’s exception score would be higher than 34 based on MMaT calculation, the candidate’s score will be capped at 34 MMaT Calculation OPTN will re-calculate MMaT every 180 days using the previous 365-day cohort At 180 day update: if MMaT increases, candidates with existing standardized score will be assigned the increased score immediately If MMaT decreases at the 180 day update, candidates with existing standardized score will not be assigned a decreased score until candidate is due for an extension. (Please Comment - the Committee prefers to revise this, to make all candidates receive new score at 6 month update) The Committee also discussed whether to retain the “cap” aspect of the current HCC exception score policy. The Committee agreed that the cap of 34 should remain in place for HCC candidates, and ultimately agreed it should be extended to all adult candidates with approved standardized exceptions, except HAT. This follows a practice that is already adopted in Region 4 that caps non-standardized exceptions at a MELD score of 34. This would help achieve greater nationwide uniformity, by preventing candidates in regions with particularly high MMaTs from receiving an undue advantage under the new policy. It also provides greater access for candidates that are registered according to their lab MELD instead of an exception. UNOS will re-calculate the median allocation MELD at transplant every 180 days using the previous 365-day cohort. If there have been fewer than 10 transplants in the DSA in the previous 365 days, the median MELD at transplant will be calculated for the region where the candidate is registered. At each 180 day update, if the median MELD increases, candidates with existing standardized score exceptions will be assigned the increased score to match the re-calculated median MELD. However, if the median MELD decreases at the 180 day update, candidates with existing standardized score exceptions will not be assigned a score to match the re-calculated median until the candidate is due for an extension. The Committee would like feedback from the regions on the best way to transition existing exception candidates at the 6 month update. The policy as proposed prevents a candidate’s score from going down shortly after it is awarded, if for example the median meld at transplant in the DSA decreases. However, the policy as proposed could also create a scenario where two candidates with the same diagnosis would have different MELD scores following the 6 month update. The Committee is considering whether to make the policy that at the 6 month update, all candidates will be assigned the same score based on the new median MELD at transplant.

12 Adult Standard Exception PointsDiagnosis Current Exception Points Assignment Recommended Proposed Exception Points Assignment Cholangiocarcinoma MELD 22 (w/ 10% point escalator) MMaT – 3 for DSA Cystic Fibrosis Familial amyloid polyneuropathy Hepatic artery thrombosis MELD 40 MELD 40 for DSA Hepatopulmonary syndrome MELD 22 (w/ 10% point escalator if PaO2 remains under 60 mmHg) Portopulmonary hypertension MELD 22 (w/ 10% point escalator if repeat heart cath shows MPAP <35) Primary Hyperoxaluria MELD 28 (w/ 10% point escalator) MMaT for DSA HCC Delay 6 months, then 28, 30, 32, 34 MMaT - 3 for DSA (after delay) As I mentioned, in addition to creating the structure of the NLRB, we are also proposing changes to the way in which exception points are assigned for standardized exceptions. We agreed that the current exception points policy is problematic in two ways: 1) it is not uniformly applied, so candidates in different regions receive different points values for similar conditions, leading to inequity in access to transplant; and 2) the MELD elevator contributes to MELD inflation, which in turn increases the waitlist mortality for non-exception candidates and drives non-exception candidates to be transplanted at higher MELD scores. We propose changing policy to assign exception points based on a “fixed floor” (certain value below MMaT in the DSA) to help solve both of these problems: it would standardize the assignment of exception points for the same diagnoses across the country, and would reduce inflation of exception scores. We debated between assigning standardized exception points equal to MMaT minus three or minus five after reviewing LSAM analyses. Though MMaT minus three is close to status quo, as candidates with exceptions now are generally transplanted with a score about three points below the MMaT, with the exception of two regions, we ultimately propose this standard because we are concerned MMaT minus five would result in too significant of a change, especially given the other aspects of the exception process that are also proposed to change. This option achieves the goal of standardizing the award of exception points for the same diagnoses across the country while tying them to the local allocation unit, and also is an incremental change that introduces the concept of the fixed floor while removing the elevator. We also considered whether, for adult candidates, the fixed floor should apply to all diagnoses, some diagnoses, or only to HCC exception candidates. We agreed that there are two diagnoses that should be excluded from the MMaT minus three approach due to their disparate waitlist mortality risks: hepatic artery thrombosis (HAT) and primary hyperoxaluria. MMaT = Median MELD at Transplant

13 Pediatric Standard Exception Points for Candidates 12-17 years oldDiagnosis Current Exception Points Assignment Recommended Proposed Initial Exception Points Assignment for year olds Cholangiocarcinoma MELD 22/PELD 28 (w/ 10% elevator) MMaT for DSA Cystic Fibrosis Familial amyloid polyneuropathy Hepatic artery thrombosis (not meeting 1A criteria) MELD 40 MELD or a PELD 40 Hepatopulmonary syndrome Metabolic Disease MELD/PELD 30, then status 1B after 30 days MMaT for DSA, then 1B after 30 days Portopulmonary hypertension Primary Hyperoxaluria MELD 28/PELD 41 (w/ 10% elevator) MMaT for DSA + 3 HCC MELD 28/PELD 41 (w/ elevator) We also sought input from pediatric specialists regarding whether and how the fixed points concept should apply to pediatric candidates less than 18 years old seeking a standardized exception. We realized that retaining status quo for the pediatric points assignment would disadvantage pediatric candidates with standardized MELD/PELD exceptions in the new proposed system for adult points assignments, because the pediatric scores set by existing policy would almost always be less than the median MELD at transplant in the DSA. For most diagnoses, we agreed that candidates meeting the criteria for the standardized exceptions should receive a score equal to the median MELD at transplant. The vast majority of pediatric patients with exceptions have non-standard exceptions. These very few pediatric candidates who are transplanted with standard exceptions may receive a slight advantage over adult candidates, and this was based on the implications of delayed access to transplantation on growth and development. HAT continues to receive a score of 40. Pediatric candidates qualifying for a standard exception for primary hyperoxaluria would receive a score equal to 3 points above the MMaT. The cohort for this calculation is slightly different than the adults: for adults, the cohort includes all adult liver transplant recipients over the last year. For pediatric candidates, the Committee proposes different cohorts for candidates between 12 to 17 years old and for candidates less than 12 years old. For candidates between 12 to 17 years old, the Committee proposes that the cohort includes all liver recipients over the last year. The Committee determined it is important that the cohort used for this age group includes pediatric candidates because it applies to them, but cannot be limited to pediatric candidates because the cohort would be too small and variable.

14 Pediatric Standard Exception Points for Candidates < 12 years oldDiagnosis Current Exception Points Assignment Recommended Proposed Initial Exception Points Assignment for less than 12 year olds Cholangiocarcinoma MELD 22/PELD 28 (w/ 10% elevator) MMaT for region Cystic Fibrosis Familial amyloid polyneuropathy Hepatic artery thrombosis (not meeting 1A criteria) MELD 40 MELD or a PELD 40 Hepatopulmonary syndrome Metabolic Disease MELD/PELD 30, then status 1B after 30 days MMaT for region, then 1B after 30 days Portopulmonary hypertension Primary Hyperoxaluria MELD 28/PELD 41 (w/ 10% elevator) MMaT for region + 3 HCC MELD 28/PELD 41 (w/ elevator) The Committee determined that the calculation for pediatric candidates less than 12 should be based on the median MELD at transplant for the region instead of the DSA. This is because candidates less than 12 years old compete for organs from pediatric donors in their region, rather than just in their DSA. It is therefore fair to make their scores standard across the region.

15 Supporting Evidence SRTR Modeling examined 1-5 points below MMaT of all recipients in the DSA where the candidate is listed Proportion of candidates with no exceptions undergoing transplant is estimated to increase as awarded exception points in a scenario decrease. MMaT – 3 not projected to increase waitlist mortality The Committee requested that the SRTR simulate alternative exception point scoring scenarios that award exception points at a certain level (between minus 1 to minus 5) below the median allocation MELD/PELD at transplant (MMaT) in the DSA. The analysis showed that the proportion of candidates with no exceptions undergoing transplant is estimated to increase as the awarded exception points in a scenario decrease. Waitlist mortality rates for exception candidates may increase slightly or remain the same for HCC exception and other exception candidates compared with current policy, but minimum-maximum ranges of estimates overlap. The Committee noted that this proposed policy is not intended to impact waitlist mortality, and the Committee is satisfied that the MMaT minus three scenario is not expected to significantly increase waitlist mortality.

16 Supporting Evidence Post-Transplant Mortality rates Transplant RatesNot projected to change, and rates are similar for recipients with no exception, HCC, and other exceptions Transplant Rates May decrease slightly for all patients as the number of points assigned below MMaT increases Variation by Region Analysis showed little variation in transplant rates, waitlist mortality, and post- transplant mortality across the five scenarios Post-transplant mortality is not projected to change, and rates are similar for recipients with no exception, HCC, and other exceptions. Again, the Committee noted that this proposal is not intended to impact post-transplant mortality, and is satisfied that MMaT minus three scenario is not expected to significantly affect post-transplant mortality. Very little change is projected in transplant rate and this is shown in the next slide. The reminder of the data are shown at the end of this presentation The Committee requested that the SRTR provide this analysis stratified by region. The analysis showed little variation in transplant rates by exception status, waitlist mortality, and post-transplant mortality across the five scenarios. In all regions, the proportion of non-exception candidates undergoing transplant increases as MMaT decreases.

17 The is the data for transplant rate by exception status

18 How will members implement this proposal?Liver Transplant Programs May appoint rep and alternate to each adult specialty boards Become familiar with the NLRB Operational Guidelines Guidelines detail review board process and appeals No change to qualifying criteria for standardized exceptions in policy No additional data collection required Liver programs will have to submit required information in discrete data fields in UNet instead of in narrative form This proposal will require programming in UNet, estimated at an enterprise level. However, this programming will eliminate several manual processes for UNOS Review Board staff, which will result in long-term cost-savings. Review Board staff will still be responsible for facilitating conference calls for programs that choose to appeal a case to the NLRB after a second randomized review results in a denial. On the date of implementation, liver candidates with approved standardized MELD or PELD exception scores will either retain their existing exception scores, or will be assigned the new score according to the proposed policy, whichever value is higher. The Committee does not want to take points away from candidates who were previously approved at a higher value, but also does not want to disadvantage candidates with existing scores if their existing scores are lower than other similarly situated candidates under the newly designed exception score system. The OPTN will work with the Committee to develop the orientation training all NLRB representatives and alternates must complete before beginning their term of service. This proposal also requires an instructional program for members to educate them on changes to policy and how it will affect their work, especially the submission of exception requests.

19 How will the OPTN implement this proposal?Expected for 2017 Board Meeting UNet programming required Implementation On implementation date, candidates with approved exception scores will retain their existing score, or will be assigned the new score according to policy, whichever value is higher We’ll provide orientation training for NLRB members and instructional training for members This proposal will require programming in UNet, estimated at an enterprise level. However, this programming will eliminate several manual processes for UNOS Review Board staff, which will result in long-term cost-savings. Review Board staff will still be responsible for facilitating conference calls for programs that choose to appeal a case to the NLRB after a second randomized review results in a denial. On the date of implementation, liver candidates with approved standardized MELD or PELD exception scores will either retain their existing exception scores, or will be assigned the new score according to the proposed policy, whichever value is higher. The Committee does not want to take points away from candidates who were previously approved at a higher value, but also does not want to disadvantage candidates with existing scores if their existing scores are lower than other similarly situated candidates under the newly designed exception score system. The OPTN will work with the Committee to develop the orientation training all NLRB representatives and alternates must complete before beginning their term of service. This proposal also requires an instructional program for members to educate them on changes to policy and how it will affect their work, especially the submission of exception requests.

20 Questions? Any questions about the proposal before I move onto the guidance documents?

21 NLRB Guidance Documents

22 What problem will the proposal solve?Non-standardized exceptions informally governed by regional agreements, which vary from region to region Guidance documents complement the NLRB policy proposal Guidance provides up-to-date information on non-standard exceptions This proposal is a companion to the proposal to establish a National Liver Review Board (NLRB). For non-standardized diagnoses, most OPTN/UNOS regions have adopted independent criteria used to request and approve exceptions, commonly referred to as “regional agreements.” These regional agreements may contribute to regional differences in exception submission and award practices, even among regions with similar organ availability and candidate demographics. The guidance documents contained in this proposal will help the specialty boards make more consistent decisions by providing the reviewers with up-to-date information about the most common conditions for which exceptions are most likely to be submitted.

23 What are the proposed solutions?Guidance documents for each of the three specialty boards Adult MELD Exception Guidance Supplement existing guidance for NET, PLD, PSC, POPH Includes guidance from Fall 2016 public comment Only difference is modification to Budd Chiari and Hepatic Adenoma Pediatric Exception Guidance Brand new guidance that did not previously exist HCC Exception Guidance For those candidates that do not meet the criteria for standardized HCC exceptions If supported by the community and approved by the Board of Directors, this guidance would replace regional agreements. Review board members and transplant centers would consult this resource when considering MELD or PELD exception requests for candidates with these diagnoses, recognizing that this resource is not exhaustive of all clinical scenarios. The guidance in these documents is based on published peer-review literature, data, and clinical consensus. Additionally, the HCC guidance document contains recommendations for dynamic contrast-enhanced CT or MRI of the liver. These recommendations previously existed in policy, but recommendations, rather than rules, are not appropriate for policy. In the development of the HCC proposal in 2016, the Committee agreed to remove these two tables from policy that describe the recommended CT and MRI characteristics, and put them in the guidance document instead. We encourage you to read through all three guidance documents and provide us with feedback.

24 Adult Guidance Diagnosis Recommendation Budd Chiari*Underlined bullets are new recommendations following Fall 2017 public comment. Exception may be appropriate based on severity of liver dysfunction and failure of standard management. Documentation should include: Failed medical management Etiology of hypercoagulable state Any contraindications to TIPS or TIPS failure Decompensated portal hypertension in the form of hepatic hydrothorax requiring thoracentesis >1L per week for at least 4 weeks Extrahepatic malignancy has been ruled out Budd Chiari syndrome is an uncommon manifestation of hepatic vein thrombosis and patients might present with evidence of decompensated portal hypertension (ascites and hepatic hydrothorax) among others. Liver transplant candidates with Budd Chiari syndrome could be considered on an individual basis for a MELD exception based on severity of liver dysfunction and failure of standard management. Documentation submitted for case review should include all of the following: • Failed medical management (please specify) Etiology of hypercoagulable state • Any contraindications to TIPS or TIPS failure; you need to specify specific contraindication • Decompensated portal hypertension in the form of hepatic hydrothorax requiring thoracentesis more than 1 liter per week for at least 4 weeks (transudate, no evidence of empyema, and negative cytology or any evidence of infection). Documentation that extraphepatic malignancy has been ruled out

25 Adult Guidance Diagnosis Recommendation Multiple Hepatic Adenomas*Underlined bullets are new recommendations following Fall 2017 public comment. Exception may be appropriate in select patients with adenoma with risk of malignant transformation, not amenable to resection. Documentation should include: Reason not amenable to resection And one or more of the following: Malignant transformation suspected or proven by biopsy Presence of glycogen storage disease Orthotopic liver transplantation for hepatic adenomas remains an extremely rare indication; however, it is a valid therapeutic option in select patients with adenoma with risk of malignant transformation, not amenable to resection, Documentation should include reason not amenable to resection and one or more of the following: • Malignant transformation suspected or proven by biopsy • Presence of underlying liver disease (GSD, vascular anomalies, fibrosis or cirrhosis)

26 Pediatric Guidance Now I’m going to discuss the guidance for the NLRB members on the Pediatric specialty board.

27 Pediatric Guidance Diagnosis RecommendationStatus 1B - Chronic Liver Disease Generally, candidates not meeting Policy 9.1.C: Pediatric Status 1B Requirements should not receive a status 1B exception. Candiates meeting Policy 9.1.C.2.c or 9.1.C.2.d but without a PELD of at least 25 may be considered, if critically ill and in the ICU Candidates without renal replacement therapy may be considered for 1B, if meet criteria in policy and require a liver support device Status 1B - Neoplasm Candidates with biopsy-proven hepatoblastoma without evidence of metastatic disease qualify for status 1B. In some instances, it may also be appropriate to consider the following pediatric candidates with hepatoblastoma for a status 1B exception: Candidates less than 8 but not biopsied with No evidence of metastasis at time of listing, and AFP greater than 100 Candidates with biopsy confirmed embryonal sarcoma Candidates with vascular malformation and hospitalized with Kasabach-Merritt syndrome or high output cardiac failure. Generally candidates that do not meet criteria in Policy 9.1.C: Pediatric Status 1B Requirements should not receive a status 1B exception. Candidates that meet criteria in Policy 9.1.C.2.c or 9.1.C.2.d but without a PELD score of at least 25 may be considered for status 1B exception if the candidate is critically ill and admitted in the Intensive Care Unit (ICU). Candidates without renal replacement therapy may be considered for a status 1B exception if they meet all other criteria in policy and require a liver support device (such as Molecular Adsorbent Recirculating System (MARS), albumin dialysis, plasmapheresis). Under Policy 9.1.C.2, candidates with biopsy-proven hepatoblastoma without evidence of metastatic disease qualify for status 1B. In some instances, it may also be appropriate to consider the following pediatric candidates with hepatoblastoma for a status 1B exception: •Candidates less than 8 years old with hepatoblastoma but not biopsied with radiographic criteria consistent with unresectable hepatoblastoma, and all of the following: o No evidence of metastasis at time of listing o AFP greater than 100 •Candidates with a biopsy-confirmed embryonal sarcoma that has not metastasized , , •Candidates with vascular malformation (congenital, infantile, or other) and hospitalized with presence of Kasabach-Merritt syndrome or presence of high output cardiac failure requiring pressor or ventilatory support There is inadequate evidence to support approving Status 1B exception for pediatric candidates with rhabdoid tumors. , , , There is also inadequate evidence to support approving Status 1B exception for pediatric candidates with angiosarcoma.

28 Pediatric Guidance Diagnosis Recommendation HepatoblastomaCandidates with non-metastatic hepatoblastoma are eligible for Status 1B under Policy 9.1.C Pediatric Status 1B Epithelioid Hemangioendothelioma (HEHE) Candidates with (HEHE) with unresectable lesions unresponsive to therapy may be considered for exceptions. Candidates with non-metastatic hepatoblastoma are eligible for status 1B under Policy 9.1.C Pediatric Status 1B. Candidates with (HEHE) with unresectable lesions unresponsive to therapy may be considered for exceptions.

29 Pediatric Guidance Diagnosis RecommendationMetastatic Neuroendocrine Tumor (NET) Review board should consider the following for NET: Resection of primary malignancy and extra-hepatic disease without any evidence of recurrence for at least 6 months. Neuroendocrine Liver Metastasis (NLM) limited to the liver, bi-lobar, not amenable to resection. Tumors in the liver should meet specific characteristics on either CT or MRI Consider for exception only those with Gastro-entero-pancreatic (GEP) origin tumors with portal system drainage. Metastatic Neuroendocrine Tumor (NET) A review of the literature supports that candidates with NET are expected to have a low risk of waiting list drop-out, though they benefit from transplantation. The Review Board should consider the following criteria when reviewing exception applications for candidates with NET: Resection of primary malignancy and extra-hepatic disease without any evidence of recurrence at least six months prior to MELD or PELD exception request. Neuroendocrine Liver Metastasis (NLM) limited to the liver, Bi-lobar, not amenable to resection. Tumors in the liver should meet the following radiographic characteristics on either CT or MRI: If CT Scan: Triple phase contrast Lesions may be seen on only one of the three phases Arterial phase: may demonstrate a strong enhancement Large lesions can become necrotic/calcified If MRI Appearance: Liver metastasis are hypodense on T1 and hypervascular in T2 wave images Diffusion restriction Majority of lesions are hypervascular on arterial phase with wash – out during portal venous phase Hepatobiliary phase post Gadoxetate Disodium (Eovist): Hypointense lesions are characteristics of NET Consider for exception only those with a NET of Gastro-entero-pancreatic (GEP) origin tumors with portal system drainage.

30 Pediatric Guidance Diagnosis Recommendation NET (continued) HCCLower- intermediate grade following the WHO classification Tumor metastatic replacement should not exceed 50% of liver volume Negative metastatic workup should include one of the following: PET scan Somatostatin receptor scintigraphy Gallium-68 labeled somatostatin analogue or other scintigraphy to rule out extra-hepatic disease. No evidence for extra-hepatic tumor recurrence based on metastatic radiologic workup at least 3 months prior. Recheck metastatic workup every 3 months for MELD or PELD increase consideration. Occurrence of extra-hepatic progression should indicate de-listing. Patients may come back to list if extra-hepatic disease is zeroed and remained for at least 6 months. Presence of exta-hepatic solid organ metastases should be a permanent exclusion criteria. HCC Status 1B exceptions may be considered for pediatric HCC candidates in the presence of metabolic liver disease. Extrahepatic metastasis should be an absolute contraindication, exception points for unresectable HCC limited to liver may be considered in pediatric candidates. Children do not need to be within Milan criteria • Metastatic work up no evidence of tumors outside the liver Note: NET with the primary located in the lower rectum, esophagus, lung, adrenal gland and thyroid are not candidates for automatic MELD exception. 5) Lower - intermediate grade following the WHO classification. Only well differentiated (Low grade, G1) and moderately differentiated (intermediate grade G2). Mitotic rate <20 per 10 HPF with less than 20% ki 67 positive markers. 6) Tumor metastatic replacement should not exceed 50% of the total liver volume 7) Negative metastatic workup should include one of the following: a. Positron emission tomography (PET scan) b. Somatostatin receptor scintigraphy c. Gallium-68 (68Ga) labeled somatostatin analogue 1,4,7,10-tetraazacyclododedcane-N, N′, N″,N′″-tetraacetic acid (DOTA)-D-Phe1-Try3–octreotide (DOTATOC), or other scintigraphy to rule out extra-hepatic disease, especially bone metastasis. Note: Exploratory laparotomy and or laparoscopy is not required prior to MELD or PELD exception request. 8) No evidence for extra-hepatic tumor recurrence based on metastatic radiologic workup at least 3 months prior to MELD or PELD exception request (submit date). 9) Recheck metastatic workup every 3 months for MELD or PELD exception increase consideration by the Review Board. Occurrence of extra-hepatic progression – for instance lymph-nodal Ga68 positive locations – should indicate de-listing. Patients may come back to the list if any extra-hepatic disease is zeroed and remained so for at least 6 months. 10) Presence of extra-hepatic solid organ metastases (i.e. lungs, bones) should be a permanent exclusion criteria HCC Status 1B exceptions may be considered for pediatric candidates with HCC in the presence of metabolic liver disease (such as hereditary tyrosinemia).

31 Pediatric Guidance Diagnosis Recommendation HCCStatus 1B exceptions may be considered for pediatric HCC candidates in the presence of metabolic liver disease. Extrahepatic metastasis should be an absolute contraindication but exception points for unresectable HCC limited to liver may be considered on a case by case basis in pediatric candidates. Children do not need to be within Milan criteria Documentation of metastatic work up (including cross-sectional imaging of the chest and bone scan or PET) and no evidence of tumors outside the liver Hilar Cholangiocarcinoma May be considered for MELD or PELD exception if candidate meets requirements in Policy 9.3.E: Candidates with Cholangiocarcinoma Growth Failure or Nutritional Insufficiency Insufficient evidence to support approval of exception points for pediatric candidates with any broadly defined growth failure or nutritional insufficiency. Exception should be considered for candidates meeting the following criteria: Growth Parameters - <5th percentile for height, weight. Z-score less than 2 standard deviations Anthropometrics - skin fold thickens < 5th percentile Failure of nasoenteric tube feedings Requirement for TPN nutrition HCC Status 1B exceptions may be considered for pediatric candidates with HCC in the presence of metabolic liver disease (such as hereditary tyrosinemia). The review board may award exceptions for candidates with HCC in certain circumstances. In the absence of metabolic disease, data from the Pediatric Liver Unresectable Tumor Observatory (PLUTO) registry and other single center experience suggests criteria may be expanded beyond Milan and University of California – San Francisco (UCSF) criteria. Extrahepatic metastasis should be an absolute contraindication but exception points for unresectable HCC limited to liver may be considered on a case by case basis in pediatric candidates. • Children do not need to be within Milan criteria • Documentation of metastatic work up (including cross-sectional imaging of the chest and bone scan or PET) and no evidence of tumors outside the liver Hilar Cholangiocarcinoma Candidates with hilar cholangiocarcinoma may be considered for a MELD or PELD exception if the candidate meets the requirements in Policy 9.3.E: Candidates with Cholangiocarcinoma Growth Failure or Nutritional Insufficiency There is insufficient evidence to support approval of exception points for pediatric candidates with any broadly defined growth failure or nutritional insufficiency. However, exceptions should be considered for candidates who meet any of the following criteria: • Growth parameters o For candidates over 1 year of age, <5th percentile for: height, weight (may adjust to estimated dry weight if ascites) , o Z-score (Weight for height) less than 2 standard deviations • Anthropometrics o Skin fold thickness < 5th percentile for age and gender for children > 1 year • Failure of nasoenteric tube feedings as evidenced by failure to demonstrate improvement in growth failure in the previous month based on either weight or anthropometrics • Requirement for TPN nutrition to allow for growth or to maintain euglycemia

32 Pediatric Guidance Diagnosis Recommendation InfectionsMELD or PELD exception points candidates with recurrent cholangitis or other life-threatening infection may be appropriate. Documentations submitted should indicate one of the following: Two or more episodes of spontaneous bacterial peritonitis At lease one episode of other life-threatening infection with sepsis requiring ICU stay Two or more episodes of cholangitis within 6 months requiring IV antibiotics Complications of portal hypertension, including ascites Approval of MELD or PELD exception points for hospitalized pediatric candidates with complications of portal hypertension may be appropriate. Documentation submitted for case review should indicate: Gastrointestinal bleeding with on-going transfusion requirement Transjugular intrahepatic portosystemic shunt (TIPS) placement as a bridge to transplant. Indicate if TIPS is not an option or variceal bleeding unresponsive to ablative therapy Ongoing octreotide administration Insufficient evidence for exception points in splenomegaly or varices without bleeding and insufficient evidence to support points for ascites controlled by diuretics in the outpatient setting. Points may be considered for: Serum sodium less than 130, two times greater than 2 weeks apart Multiple therapeutic paracenteses Hydrothorax requiring chest tube or therapeutic thoracentesis Approval of MELD or PELD exception points for pediatric candidates with recurrent cholangitis or other life-threatening infection may be appropriate in some instances. Documentation submitted for case review should indicate one of the following: • Two or more episodes of spontaneous bacterial peritonitis (SBP) (specify date of each episode) • At least one episode of other life-threatening infection with sepsis requiring ICU stay • Two or more episodes of cholangitis within 6 months requiring IV antibiotics requiring placement of a PICC or central line for > 2 continuous weeks for ongoing administration of antibiotics (specify date of each episode) Complications of portal hypertension, including ascites Approval of MELD or PELD exception points for hospitalized pediatric candidates with complications of portal hypertension may be appropriate in some instances. Documentation submitted for case review should indicate: • Gastrointestinal bleeding with on-going transfusion requirement • Transjugular intrahepatic portosystemic shunt (TIPS) placement as a bridge to transplant. Indicate if TIPS is not an option or variceal bleeding unresponsive to ablative therapy • Ongoing octreotide administration There is insufficient evidence to support approval of exception points in the presence of splenomegaly or varices without bleeding. There is also insufficient evidence to support approval of exception points for pediatric candidates with ascites controlled by diuretics in the outpatient setting. Exception points may be considered for candidates with severe or complicated ascites in at least one of the following clinical scenarios: • Serum sodium less than 130, two times greater than 2 weeks apart • Multiple therapeutic paracenteses (at least 2 in the previous 30 days, not including diagnostic paracentesis) • Hydrothorax requiring chest tube or therapeutic thoracentesis

33 Pediatric Guidance Diagnosis Recommendation EncephalopathyMELD or PELD exception points for hospitalized candidates with symptomatic encephalopathy may be appropriate in any of the following: Clinically refractory to medical management with lactulose or rifaximin Infant Glasgow coma score less than 12 Hepatopulmonary Syndrome Approval of additional MELD or PELD exception points for pediatric candidates who meet the standardized criteria for hepatopulmonary syndrome may be appropriate in some instances, such as if the candidate is hospitalized, or if the candidate is debilitated or exhibits progressive decompensation. Developmental Delay Insufficient evidence to support exception points Pruritus Approval of MELD or PELD exception points for pediatric candidates with pruritus may be appropriate. Documentation submitted for case review should indicate that the candidate has evidence of cutaneous mutilation with bleeding and scratching nonresponsive to medications such as rifampin, ursodiol and naltrexone. Candidates should not be awarded additional MELD or PELD exceptions points on the basis of xanthomas or an indwelling biliary catheter. Encephalopathy Approval of MELD or PELD exception points for hospitalized pediatric candidates with symptomatic encephalopathy may be appropriate in any of the following instances: • Clinically refractory to medical management with lactulose or rifaximin • Infant Glasgow coma score less than 12 Hepatopulmonary Syndrome Approval of additional MELD or PELD exception points for pediatric candidates who meet the standardized criteria for hepatopulmonary syndrome according to Policy 9.3.C: Specific MELD/PELD Exceptions may be appropriate in some instances, such as if the candidate is hospitalized, or if the candidate is debilitated or exhibits progressive decompensation. Developmental Delay There is insufficient evidence to support approval of exception points for pediatric candidates with developmental delay. Pruritus Approval of MELD or PELD exception points for pediatric candidates with pruritus may be appropriate in some instances. Documentation submitted for case review should indicate that the candidate has evidence of cutaneous mutilation with bleeding and scratching nonresponsive to medications such as rifampin, ursodiol and naltrexone. Candidates should not be awarded additional MELD or PELD exceptions points on the basis of xanthomas or an indwelling biliary catheter.

34 Pediatric Guidance Diagnosis Recommendation Metabolic Bone DiseaseApproval of MELD or PELD exception points for pediatric candidates with metabolic bone disease may be appropriate. Documentation submitted for case review should indicate: • Documented pathologic fractures or bone deformity • Patient is unresponsive to vitamin D, mineral supplementation Congenital Portosystemic Shunts Pediatric patients with congenital portosystemic shunts as Abernathy syndrome may be evaluated on the basis of their complications (hyperammonemia and encephalopathy or hepatopulmonary syndrome) rather than as a unique disease category. Chronic Rejection Chronic rejection alone is not sufficient for an exception. Exceptions for clinical complications or manifestations of chronic rejection may be appropriate if the transplant program submits evidence of a comorbid condition from the Chronic Liver Disease section above, as well as other evidence including: • Evidence of chronic rejection on liver biopsy • Recurrent infections – cholangitis, spontaneous bacterial peritonitis (SBP) (similar criteria regarding quanitification and severity of infections to cholestatic patients) • Growth failure/nutritional insufficiency, complication of portal hypertension, hyponatremia – sodium less than 130, intractable ascites, intractable pruritis Metabolic Bone Disease Approval of MELD or PELD exception points for pediatric candidates with metabolic bone disease may be appropriate in some instances. Documentation submitted for case review should indicate: • Documented pathologic fractures or bone deformity • Patient is unresponsive to vitamin D, mineral supplementation Congenital Portosystemic Shunts Pediatric patients with congenital portosystemic shunts as Abernathy syndrome may be evaluated on the basis of their complications (hyperammonemia and encephalopathy or hepatopulmonary syndrome) rather than as a unique disease category. Chronic rejection Chronic rejection (CR) may cause long-term graft dysfunction and fibrosis. The Banff group defined the minimal histological features of CR as biliary epithelial changes affecting a majority of bile ducts with or without duct loss, foam cell obliterative arteriopathy, or bile duct loss affecting greater than 50% of portal tracts. , In the Studies of Pediatric Liver Transplantation (SPLIT) database, CR remains at a less than 5% incidence; however 38% of reported patients proceeded to retransplanation. When evaluating late graft loss (more than one year after transplant), 37% of all lost grafts in SPLIT were due to CR. Retransplantation is indicated for those patients who do not respond to treatment of rejection. Chronic rejection alone is not sufficient for an exception. Exceptions for clinical complications or manifestations of chronic rejection may be appropriate if the transplant program submits evidence of a comorbid condition from the Chronic Liver Disease section above, as well as other evidence including: • Evidence of chronic rejection on liver biopsy • Recurrent infections – cholangitis, spontaneous bacterial peritonitis (SBP) (similar criteria regarding quanitification and severity of infections to cholestatic patients) • Growth failure/nutritional insufficiency, complication of portal hypertension, hyponatremia – sodium less than 130, intractable ascites, intractable pruritis

35 Pediatric Guidance Diagnosis Recommendation CholangiopathyExceptions for clinical complications or manifestations of chronic graft dysfunction due to biliary cause may be appropriate if the transplant program submits evidence of a comorbid condition from the Chronic Liver Disease section above, as well as other evidence including: • Radiological evidence (imaging study such as MR; percutaneous or endoscopic findings of cholangiopathy) of cholangiopathy is required specify: • Recurrent infections/cholangitis, including: o development or evolution of bacterial resistance o SBP o Growth failure/nutritional insufficiency o Complication of portal hypertension o Hyponatremia – sodium less than 130 o Intractable ascites o Intractable pruritis Late HAT Patients with early HAT just beyond the 7 day status 1A cut off or the 14 day standard exception cut off with evidence of severe graft dysfunction may be considered for MELD exception, depending on the clinical scenario. Cholangiopathy Exceptions for clinical complications or manifestations of chronic graft dysfunction due to biliary cause may be appropriate if the transplant program submits evidence of a comorbid condition from the Chronic Liver Disease section above, as well as other evidence including: • Radiological evidence (imaging study such as MR; percutaneous or endoscopic findings of cholangiopathy) of cholangiopathy is required specify: • Recurrent infections/cholangitis, including: o development or evolution of bacterial resistance o SBP (similar criteria regarding quantification and severity of infections to cholestatic patients) o Growth failure/nutritional insufficiency o Complication of portal hypertension o Hyponatremia – sodium less than 130 o Intractable ascites o Intractable pruritis Late HAT A definitive diagnosis of late HAT requires more advanced imaging (e.g. CT, MR, or standard angiographies). If treatment is required, thrombolysis and anticoagulation are rarely effective, and surgical reconstruction is contraindicated. Radiological treatment of biliary strictures is indicated if necessary, and drainage of intrahepatic abscesses/bilomas is required. For symptomatic late HAT with cholangitis, hepatic abscesses, or diffuse biliary stricturing, retransplantation is frequently necessary. Specific information regarding the following is helpful to substantiate the request: • Radiological or angiographic evidence of HAT complicated by both of the following: o Recurrent infections – cholangitis, sepsis o Failure or inapplicability of percutaneous or endoscopic biliary interventions: specify Patients with early HAT just beyond the 7 day status 1A cut off or the 14 day standard exception cut off with evidence of severe graft dysfunction may be considered for MELD exception, depending on the clinical scenario.

36 Pediatric Guidance Diagnosis RecommendationPortal Vein Thrombosis (PVT) Data requested for exception requests should include: Evidence of PVT on imaging study or angiography required with complication requiring retranplantation (i.e. refractory complications of portal hypertension, hepatopulmonary syndrome) Contraindication to surgical shunt: specify Failure of surgical shunt: specify Portal Vein Thrombosis (PVT) , PVT is estimated at 2-10% in all pediatric recipients. Portal hypertensive complications manifest mostly as hypersplenism and gastrointestinal (GI) bleeding. Currently scarce systematic data is available on those patients' outcomes. Surgical shunts (selective distal splenorenal, systemic mesocaval, and meso-Rex) are useful, but retransplantation may be indicated. A REX shunt (meso-rex bypass) is favored when technically feasible. Endovascular interventions should be attempted in patients with portal vein stenosis. Data requested to substantiate exception requests include: • evidence of PVT on imaging study or angiography required with complication requiring retranplantation (i.e. refractory complications of portal hypertension, hepatopulmonary syndrome) • Contraindication to surgical shunt: specify • Failure of surgical shunt: specify

37 Adult HCC Guidance

38 Adult HCC Guidance 1. Patients with the following are contraindications for HCC exception score: Macro-vascular invasion of main portal vein or hepatic vein Extra-hepatic metastatic disease Ruptured HCC T1 stage HCC HCC MELD exception may be appropriate for patients with macro-vascular invasion of branch portal vein and ruptured HCC. 2. Patients who have a history of prior HCC >2 years ago which was completely treated with no evidence of recurrence, who develop new or recurrent lesions after 2 years should generally be considered the same as those with no prior HCC, in order to determine the current stage suitability for MELD exception, and MELD exception score assignment. The Committee proposed guidance for candidates with HCC presenting outside of standardized criteria. These two slides detail the guidance provided to NLRB members. The Committee provides several contraindications for and HCC exception score, these include: Macro-vascular invasion of main portal vein or hepatic vein Extra-hepatic metastatic disease Ruptured HCC T1 stage HCC Additionally candidates with macro-vascular invasion of branch portal vein and ruptured HCC may be appropriate for exception. The Committee also proposes guidance for candidates with history of prior HCC .

39 Adult HCC Guidance 3. Patients beyond standard criteria who have continued progression while waiting despite LRT are generally not acceptable candidates for HCC MELD exception. 4. Patients with AFP>1000 who do not respond to treatment to achieve an AFP below 500 are not eligible for standard MELD exception, and must be reviewed by the HCC review board to be considered. In general, these patients are not suitable for HCC MELD exception but may be appropriate in some cases. 5. Patients with HCC beyond standard down-staging criteria who are able to be successfully downstaged to T2 may be appropriate for MELD exception, as long as there is no evidence of metastasis outside the liver, or macrovascular invasion, or AFP >1,000. Imaging should be performed at least 4 weeks after last down-staging treatment. Patients must still wait for 6 months from the time of the first request to be eligible for an HCC exception score. In addition to the previous guidance, the Committee proposes that candidates with continued progression while waiting despite local-regional treatment are generally not recommended for exception. Patients with AFP that fall out of standard criteria approved by the Board of Directors in December 2016 are generally not suitable for HCC MELD exception. And Finally, patients beyond the standard criteria for downstaging approved by the Board of Directors in December 2016 may be appropriate for MELD exception, as long as there is no evidence of metastasis outside the liver, or and AFP greater than 1000. The guidance also includes recommendations for dynamic contrast-enhanced CT or MRI of the liver. These recommendations previously existed in policy, but recommendations, rather than rules, are not appropriate for policy. In the development of the HCC proposal in 2016, the Committee agreed to remove these two tables from policy that describe the recommended CT and MRI characteristics, and put them in the guidance document instead. Guidance also includes recommendations for Dynamic Contrast-enhanced CT and MRI of the Liver

40 How will members implement this proposal?Review board members should consult this resource when assessing exception requests Members will not need to do anything if these guidance documents are approved, but they are a resource that should be consulted when considering applying for non-standardized exceptions.

41 How will the OPTN implement this proposal?Develop orientation training for all NLRB representatives and alternates Representatives must complete training before beginning their term of service Guidance will be implemented immediately upon Board approval, and can be used by RRBs until the NLRB is implemented The OPTN/UNOS will work with the Committee to develop the orientation training all NLRB representatives and alternates must complete before beginning their term of service. The content of this guidance will be included as part of that training.

42 Questions? Ryutaro Hirose, MD Committee Chair Matt Prentice, MPH Project Lead Questions, please contact UNOS staff liaison, Matt Prentice or the Chair of the Committee, Ryo Hirose.

43 Supplementary Slides

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