Description:
Transplantation of a healthy pancreas is a treatment method for patients with insulin-dependent diabetes. Pancreas transplantation can restore glucose control and is intended to prevent, halt, or reverse the secondary complications from diabetes.

For individuals who have insulin-dependent diabetes who receive a pancreas transplant after a kidney transplant, the evidence includes case series and registry studies. Relevant outcomes are overall survival, change in disease status, and treatment-related mortality and morbidity. Data from national and international registries have found relatively high patient survival rates with a pancreas transplant after a kidney transplant (e.g., a 3-year survival rate of 93%). A 2012 analysis of data from a single center found similar patient survival and death-censored pancreas graft survival rates with a pancreas transplant after a kidney transplant or a simultaneous pancreas and kidney (SPK) transplant. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have insulin-dependent diabetes with uremia who receive SPK transplant, the evidence includes registry studies. Relevant outcomes are overall survival, change in disease status, and treatment-related mortality and morbidity. Data from national and international registries have found relatively high patient survival rates after SPK transplant. A retrospective analysis found a higher survival rate in patients with Type 1 diabetes who had an SPK transplant vs those on a waiting list. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have insulin-dependent diabetes and severe complications who receive pancreas transplant alone, the evidence includes registry studies. Relevant outcomes are overall survival, change in disease status, and treatment-related mortality and morbidity. Data from International and national registries have found that graft and patient survival rates after pancreas transplant alone have improved over time (e.g., 3-year survival of 95%). The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have had a prior pancreas transplant who still meet criteria for a pancreas transplant who receive pancreas retransplantation, the evidence includes case series and registry studies. Relevant outcomes are overall survival, change in disease status, and treatment-related mortality and morbidity. National data and data reported from specific transplant centers have generally found similar graft and patient survival rates after pancreas retransplantation compared with initial transplantation. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Background
Solid organ transplantation offers a treatment option for patients with different types of end-stage organ failure that can be lifesaving or provide significant improvements to a patient’s quality of life.² Many advances have been made in the last several decades to reduce perioperative complications. Available data supports improvement in long-term survival as well as improved quality of life particularly for liver, kidney, pancreas, heart, and lung transplants. Allograft rejection remains a key early and late complication risk for any organ transplantation. Transplant recipients require life-long immunosuppression to prevent rejection. Patients are prioritized for transplant by mortality risk and severity of illness criteria developed by Organ Procurement and Transplantation Network and United Network of Organ Sharing.

Allogeneic Pancreas Transplant
In 2019, 39,719 transplants were performed in the United States procured from almost 11,900 deceased donors and 7,400 living donors.³ Pancreas-kidney transplants were the fifth most common procedure, with 872 transplants performed in 2019. Pancreas-alone transplants were the sixth most common procedure, with 143 transplants performed in 2019.

Pancreas transplantation occurs in several different scenarios such as (1) a diabetic patient with renal failure who may receive a simultaneous cadaveric pancreas plus kidney transplant; (2) a diabetic patient who may receive a cadaveric or living-related pancreas transplant after a kidney transplantation (pancreas after kidney); or (3) a nonuremic diabetic patient with specific severely disabling and potentially life-threatening diabetic problems who may receive a pancreas transplant alone.

Data from the United Network for Organ Sharing and the International Pancreas Transplant Registry indicate that the proportion of simultaneous pancreas plus kidney transplant recipients worldwide who have Type 2 diabetes has increased over time, from 6% of transplants between 2005 and 2009 to 9% of transplants between 2010 and 2014.⁴ Between 2010 and 2014, approximately 4% of pancreas after kidney transplants and 4% of pancreas alone transplants were performed in patients with Type 2 diabetes. In 2018, patients with type 2 diabetes accounted for 14.8% of all pancreas transplants, according to data from the Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients.¹ Patients with Type 2 diabetes accounted for 1.1%, 10.3%, and 16.7% of pancreas alone, pancreas after kidney, and simultaneous pancreas plus kidney transplants, respectively.

Regulatory Status
Solid organ transplants are a surgical procedure and, as such, are not subject to regulation by the U.S. Food and Drug Administration (FDA).

The FDA regulates human cells and tissues intended for implantation, transplantation, or infusion through the Center for Biologics Evaluation and Research, under Code of Federal Regulation Title 21, parts 1270 and 1271. Solid organs used for transplantation are subject to these regulations.

Related Policies
70301 Kidney Transplant
70312 Islet Transplantation

Policy
A combined pancreas-kidney transplant may be considered MEDICALLY NECESSARY in insulin-dependent diabetic patients with uremia.

Pancreas transplant after a prior kidney transplant may be considered MEDICALLY NECESSARY in patients with insulin dependent diabetes.

Pancreas transplant alone may be considered MEDICALLY NECESSARY in patients with severely disabling and potentially life-threatening complications due to hypoglycemia unawareness and labile insulin dependent diabetes that persists in spite of optimal medical management.

Pancreas retransplant after a failed primary pancreas transplant may be considered MEDICALLY NECESSARY.

Pancreas transplant is investigational and/or unproven and therefore NOT MEDICALLY NECESSARY in all other circumstances.

Policy Guidelines
General
Potential contraindications subject to the judgment of the transplant center:

1. Known current malignancy, including metastatic cancer
2. Recent malignancy with high risk of recurrence
3. Untreated systemic infection making immunosuppression unsafe, including chronic infection
4. Other irreversible end-stage disease not attributed to kidney or pancreatic disease
5. History of cancer with a moderate risk of recurrence
6. Systemic disease that could be exacerbated by immunosuppression
7. Psychosocial conditions or chemical dependency affecting ability to adhere to therapy

Pancreas Specific
Candidates for pancreas transplant alone should additionally meet 1 of the following severity of illness criteria:

• Documentation of severe hypoglycemia unawareness as evidenced by chart notes or emergency room visits; OR
• Documentation of potentially life-threatening labile diabetes as evidenced by chart notes or hospitalization for diabetic ketoacidosis.

In addition, the vast majority of pancreas transplant patients will have Type 1 diabetes mellitus. Those transplant candidates with Type 2 diabetes mellitus, in addition to being insulin-dependent, should also not be obese (body mass index [BMI] should be 32 or less). According to International registry data, in 2010, 7% of pancreas transplant recipients had Type 2 diabetes.³

Multiple Transplants
Although there are no standard guidelines regarding multiple pancreas transplants, the following information may aid in case review:

• If there is early graft loss resulting from technical factors (e.g., venous thrombosis), a retransplant may generally be performed without substantial additional risk.
• Long-term graft losses may result from chronic rejection, which is associated with increased risk of infection following long-term immunosuppression, and sensitization, which increases the difficulty of finding a negative cross-match. Some transplant centers may wait to allow reconstitution of the immune system before initiating retransplant with an augmented immunosuppression protocol

Benefit Application
BlueCard^®/National Account Issues
Transplant requests should be reviewed by the Plan medical director or his or her designee. Only patients accepted for transplantation by an approved transplantation center and actively listed for transplant should be considered for pre-certification or prior approval. Guidelines should be followed for transplant network or consortiums, if applicable.

Pancreas transplants should be considered for coverage under the transplant benefit.

What is covered under the scope of the human organ transplant (HOT) benefit needs to be considered. Typically, the following are covered under the HOT benefit:

• Hospitalization of the recipient for medically recognized transplants from a donor to a transplant recipient;
• Evaluation tests requiring hospitalization to determine the suitability of both potential and actual donors, when such tests cannot be safely and effectively performed on an outpatient basis;
• Hospital room, board, and general nursing in semi-private rooms;
• Special care units, such as coronary and intensive care;
• Hospital ancillary services;
• Physicians’ services for surgery, technical assistance, administration of anesthetics, and medical care;
• Acquisition, preparation, transportation, and storage of organ;
• Diagnostic services;
• Drugs that require a prescription by federal law.

Expenses incurred in the evaluation and procurement of organs and tissues are benefits when billed by the hospital. Included in these expenses may be specific charges for participation with registries for organ procurement, operating rooms, supplies, use of hospital equipment, and transportation of the tissue or organ to be evaluated.

Administration of products with a specific transplant benefit needs to be defined as to:

• When the benefit begins (at the time of admission for the transplant or once the patient is determined eligible for a transplant, which may include tests or office visits prior to transplant);
• When the benefit ends (at the time of discharge from the hospital or at the end of required follow-up, including the immunosuppressive drugs administered on an outpatient basis).

Coverage usually is not provided for:

• HOT services, for which the cost is covered/funded by governmental, foundational, or charitable grants;
• Organs sold rather than donated to the recipient;
• An artificial organ.

Rationale
This evidence review was created in December 1996 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through June 30, 2023.

This evidence review was informed in part by a TEC Assessment (1998), which focused on pancreas graft survival and health outcomes associated with both pancreas transplant alone (PTA) and pancreas after kidney (PAK) transplants.⁶ A TEC Assessment (2001) focused on pancreas retransplant also informed this evidence review.⁷ These assessments and subsequent evidence offer the following observations and conclusions.

Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life, and ability to function-including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent 1 or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., people of color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (lesbian, gay, bisexual, transgender, queer, intersex, asexual); women; and people with disabilities [physical and invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Much of the published literature consists of retrospective data reported by single centers and registry data. The extant RCTs compare immunosuppression regimens and surgical techniques and therefore do not compare pancreas transplantation with insulin therapy, or simultaneous pancreas and kidney (SPK) transplant with insulin therapy and hemodialysis.

Pancreas Transplant After Kidney Transplant
Clinical Context and Therapy Purpose
The purpose of a pancreas after kidney (PAK) transplant in individuals who have insulin-dependent diabetes is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with insulin-dependent diabetes.

Interventions
The therapy being considered is a PAK transplant.

Pancreas after kidney transplantation permits patients with insulin-dependent diabetes to benefit from a living-related kidney graft, if available, and to benefit from a subsequent pancreas transplant that is likely to improve quality of life compared with a kidney transplant alone. Patients with insulin-dependent diabetes for whom a cadaveric kidney graft is available, but a pancreas graft is not simultaneously available, benefit similarly from a later pancreas transplant.

Comparators
The following therapy is currently being used to make decisions about insulin-dependent diabetes: insulin therapy.

Outcomes
The general outcomes of interest are overall survival (OS), disease progression, graft failure, and adverse events. In the short-term (post-surgery), follow-up monitors for graft failure. Long-term follow-up has extended to 10 years as survival improves.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Within each category of study design, studies with larger sample sizes and longer duration were preferred.
• Studies with duplicative or overlapping populations were excluded.

Review of Evidences
Registry Studies and Retrospective Studies
As reported by Gruessner and Gruessner (2016), according to United Network for Organ Sharing (UNOS) and International Pancreas Transplant Registry data, patient survival rates after PAK conducted from 2010 to 2014 were 97.9% after 1 year and 94.5% after 3 years.⁴ This compares with 1-year (96.4%) and 3-year (93.1%) patient survival rates for transplants conducted from 2005 to 2009.

Parajuli et al. (2019) described a single center's experience with 635 pancreas and kidney transplant patients (611 SPK, 24 PAK).⁸ Transplants were performed between 2000 and 2016. The mean length of time between kidney transplant and pancreas transplant was 23.8 months in the PAK group. Pancreas rejection rates at 1 year post-transplant were 4% and 9% with PAK and SPK respectively (p = .39). During the entire study period, PAK patients were more likely to experience pancreas rejection (38% vs. 16%; p = .005). Kidney and pancreas graft survival rates did not differ between groups at 1 year or at last follow-up. Pancreas graft survival rates for PAK and SPK at 1 year were 100% and 89%, respectively (p = .09). Death-censored pancreas graft failure rates for PAK and SPK at last follow-up were 13% and 25%, respectively (p = .17). Patient survival at last follow-up was similar between groups (71% with PAK vs. 68% with SPK; p = .79).

Bazarbachi et al. (2013) reviewed a single center's experience with PAK and SPK.⁹ Between 2002 and 2010, 172 pancreas transplants were performed in diabetic patients (123 SPK, 49 PAK). The median length of time between kidney transplant and pancreas transplant in the PAK group was 4.8 years. Graft and patient survival rates were similar for both groups. Death-censored pancreas graft survival rates for SPK and PAK were 94% and 90% at 1 year, 92% and 90% at 3 years, and 85% and 85% at 5 years (p = .93), all respectively. Patient survival rates (calculated from the time of pancreas transplantation) in the SPK and PAK groups were 98% and 100% after 1 year, 96% and 100% after 3 years, and 94% and 100% after 5 years (p = .09), respectively.

Fridell et al. (2009) reported on a retrospective review of a single center's experience with PAK and SPK since 2003, when current induction or tacrolimus immunosuppressive strategies became standard.¹⁰ Of the 203 cases studied, 61 (30%) were PAK and 142 (70%) were SPK. One-year patient survival rates were 98% PAK and 95% SPK (p = .44). Pancreas graft survival rates at 1 year were 95% and 90%, respectively (p = .28). The authors concluded that in the modern immunosuppressive era, PAK should be considered as an acceptable alternative to SPK in candidates with an available living kidney donor.

Kleinclauss et al. (2009) retrospectively reviewed data from 307 diabetic kidney transplant recipients from a single center and compared renal graft survival rates in those who subsequently received a pancreatic transplant with those who did not.¹¹ The comparative group was analyzed separately based on whether patients were medically eligible for pancreas transplant, but chose not to proceed for financial or personal reasons, or were ineligible for medical reasons. The ineligible (n = 57) group differed significantly at baseline from both the PAK group (n = 175) and the eligible group (n = 75) with respect to age, type of diabetes, and dialysis experience; kidney graft survival rates at 1, 5, and 10 years were lower in the ineligible group (75%, 54%, and 22%, respectively; p < .001) than in the other groups (for the PAK group, 98%, 82%, and 67% vs. for the eligible group, 100%, 84%, and 62%). The authors concluded that the subsequent transplant of a pancreas after a living donor kidney transplant does not adversely affect patient or kidney graft survival rates.

Section Summary: Pancreas Transplant After Kidney Transplant
Data from national and international registries have found relatively high patient survival rates after PAK (e.g., a 3-year survival rate of 94.5%). Single-center retrospective analyses have found similar patient survival and death-censored pancreas graft survival rates after PAK and SPK transplants.

Simultaneous Pancreas Plus Kidney Transplants for Patients with Uremia
Clinical Context and Therapy Purpose
The purpose of a SPK transplant in individuals who have insulin-dependent diabetes with uremia is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals who have insulin-dependent diabetes with uremia.

Interventions
The therapy being considered is an SPK transplant.

Comparators
The following therapy is currently being used to make decisions about insulin-dependent diabetes with uremia: insulin therapy.

Outcomes
The general outcomes of interest are OS, disease progression, graft failure, and adverse events. In the short-term (post-surgery), follow-up monitors for graft failure. Long-term follow-up has extended to 10 years as survival improves.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Within each category of study design, studies with larger sample sizes and longer duration were preferred.
• Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Registry Studies and Retrospective Studies
The U.S.-based Organ Procurement and Transplant Network (OPTN) has reported a 1-year patient survival rate of 97.5% (95% confidence interval [CI], 96.9% to 98.0%) for primary SPK procedures performed between 2008 and 2015.¹² Three- and 5-year patient survival rates were 94.8% (95% CI, 93.9% to 95.5%) and 88.9% (95% CI, 87.8% to 89.9% ), respectively.

An analysis of U.K. registry data by Barlow et al. (2017) compared outcomes in patients with Type 1 diabetes and end-stage renal disease who had SPK transplants (n = 1,739) versus live donor kidney transplants (n = 370).¹³ In multivariate analysis, there was no significant association between type of transplant and patient survival (hazard ratio, 0.71; 95% CI, 0.47 to 1.06; p = .095). Simulaneous pancreas plus kidney recipients with a functioning pancreas graft had significantly better OS than those with a living donor kidney transplant (p < .001).

Simultaneous pancreas plus kidney transplants have been found to reduce mortality in patients with Type 1 diabetes. Van Dellen et al. (2013) in the U.K. reported on a retrospective analysis of data for 148 SPK patients and a wait-list control group of 120 patients.¹⁴ All patients had type 1 (insulin-dependent) diabetes. (The study also included 33 patients who had PAK and 11 patients who had PTA.) Overall mortality (mortality at any time point) was 30% (30/120) for the waiting list and 9% (20/193) for transplanted patients; the difference between groups was statistically significant (p < .001). The 1-year mortality rate was 13% (n = 16) for the waiting list and 4% (n = 8) for the transplant group (p < .001).

Sampaio et al. (2011) published an analysis of data from the UNOS database.¹⁵ Outcomes for 6,141 patients with Type 1 diabetes and 582 patients with Type 2 diabetes who underwent SPK were similar for both groups in adjusted analyses. After adjusting for other factors (e.g., body weight; dialysis time; cardiovascular comorbidities), Type 2 diabetes was not associated with an increased risk of pancreas or kidney graft failure or mortality compared with Type 1 diabetes.

Section Summary: Simultaneous Pancreas Plus Kidney Transplants for Patients With Uremia
Data from national and international registries have found relatively high patient survival rates after SPK transplants (e.g., a 3-year survival rate of 94.8% and a 5-year survival rate of 88.9% ). A retrospective analysis found a higher survival rate in patients with Type 1 diabetes who had an SPK transplant than in those on a waiting list.

Pancreas Transplant Alone for Patients With Severe Complications
Clinical Context and Therapy Purpose
The purpose of a pancreas transplant in individuals who have insulin-dependent diabetes with severe diabetic complications is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals who have insulin-dependent diabetes with severe diabetic complications.

Although pancreas transplantation is generally not considered a life-saving treatment for individuals with insulin-dependent diabetes, in a small subset of patients who experience life-threatening complications from diabetes, pancreas transplantation could be considered life-saving. Pancreas transplant alone has also been investigated in patients following total pancreatectomy for chronic pancreatitis. In addition to the immune rejection issues common to all allograft transplants, autoimmune destruction of beta cells has been observed in the transplanted pancreas, presumably from the same mechanism responsible for Type 1 diabetes.¹⁶

Most patients undergoing PTA are those with either hypoglycemic unawareness or labile diabetes. However, other exceptional circumstances may exist where patients with nonuremic Type 1 diabetes have significant morbidity risks due to secondary complications of diabetes (e.g., peripheral neuropathy) that exceed those of the transplant surgery and subsequent chronic immunosuppression. Because virtually no published evidence addresses outcomes of medical management in this very small group of exceptional diabetic patients, it is not possible to generalize about which circumstances represent appropriate indications for PTA. Case-by-case consideration of each patient's clinical situation may be the best option for determining the balance of risks and benefits.

Interventions
The therapy being considered is PTA.

Comparators
The following therapy is currently being used to make decisions about insulin-dependent diabetes with severe diabetic complications: insulin therapy.

Outcomes
The general outcomes of interest are OS, disease progression (eg, end-stage renal disease), graft failure, and adverse events (e.g., hypoglycemia, labile diabetes). In the short-term (post-surgery), follow-up monitors for graft failure. Long-term follow-up has extended to 5 years as survival improves.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Within each category of study design, studies with larger sample sizes and longer duration were preferred.
• Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Registry Studies and Retrospective Studies
Pancreas transplant graft survival has improved over time. According to International Pancreas Transplant Registry data, 1-year graft function increased from 51.5% for 1987 to 1993 to 77.8% for 2006 to 2010 (p < .001).¹⁷ One-year immunologic graft loss remained higher (6.0%) after PTA than after PAK (3.7%) or SPK (1.8%). According to UNOS and the International Pancreas Transplant Registry data, for the period from 2010 to 2014, the patient survival rate for PTA was 96.3% after 1 year and 94.9% after 3 years.⁴ This compares with 1-year and 3-year patient survival rates of 97.5% and 93.3% for 2005 to 2009, respectively. According to Gruessner (2011), in carefully selected patients with type 1 diabetes and severely disabling and potentially life-threatening complications due to hypoglycemia unawareness and persistent labile diabetes despite optimal medical management, the benefits of PTA were judged to outweigh the risk of performing pancreas transplantation with subsequent immunosuppression.¹⁷

Boggi et al. (2021) reported results of a single-center cohort study of 66 patients with Type 1 diabetes who received PTA.¹⁸ After 10 years of follow-up, patient survival was 92.4%. Of these patients surviving to 10 years, 57.4% had optimal graft function (defined as normoglycemia and insulin independence) and 3.2% had good graft function (defined as HbA1C < 7%, no severe hypoglycemia, > 50% reduction in insulin requirements, and restoration of clinically significant C-peptide production). Four patients (6.0%) developed end-stage renal failure (stage 5, estimated glomerular filtration rate [eGFR] < 15 ml/min/1.73 m2), and 2 additional patients (3.0%) showed stage 4 kidney failure (eGFR 15 to 30 ml/min/1.73 m2) at the 10-year posttransplant assessment.

Noting that nephrotoxic immunosuppression may exacerbate diabetic renal injury after PTA, Scalea et al. (2008) reported on a single institutional review of 123 patients who received 131 PTA for the development of renal failure.¹⁹ Mean graft survival was 3.3 years (range, 0 to 11.3 years), and 21 patients were lost to follow-up. At a mean follow-up of 3.7 years, the mean eGFR was 88.9 mL/min/1.73 m2 pretransplantation and 55.6 mL/min/1.73 m2 posttransplantation. All but 16 patients had a decrease in eGFR. Thirteen developed end-stage renal disease, which required kidney transplantation at a mean of 4.4 years. The authors suggested that patients should be made aware of the risk and only the most appropriate patients should be offered PTA.

Section Summary: Pancreas Transplant Alone for Patients With Severe Complications
Data from international and national registries have found that graft and patient survival rates after PTA have improved over time. For the period of 2010 to 2014, 1- and 3-year survival rates had improved to 96.3% and 94.9%, respectively.

Pancreas Retransplantation
Clinical Context and Therapy Purpose
The purpose of a pancreas retransplant in individuals who have had a prior pancreas transplant and still meet criteria for a pancreas transplant is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals who have had a prior pancreas transplant and still meet criteria for a pancreas transplant.

Interventions
The therapy being considered is a pancreas retransplant.

The approach to retransplantation varies by cause of failure. Surgical and technical complications such as venous thrombosis are the leading cause of pancreatic graft loss among diabetic patients. Graft loss from chronic rejection may result in sensitization, increasing both the difficulty of finding a cross-matched donor and the risk of rejection of a subsequent transplant. Each transplant center has guidelines based on experience; some centers may wait to allow reconstitution of the immune system before initiating retransplant with an augmented immunosuppression protocol.

Comparators
The following therapy is currently being used to make decisions about a failed pancreas transplant: insulin therapy.

Outcomes
The general outcomes of interest are OS, graft progression, transplant failure, and adverse events. In the short-term (post-surgery), follow-up monitors for graft failure. Long-term follow-up has extended over time to 5 years as survival improves.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Within each category of study design, studies with larger sample sizes and longer duration were preferred.
• Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Registry Studies and Retrospective Studies
Parajuli et al. (2019) compared outcomes among SPK patients who did or did not receive pancreas retransplantation after isolated pancreas graft failure.²⁰ Among 109 SPK patients with pancreas graft failure, 25 underwent pancreas retransplantation and 84 did not. The mean follow-up time after pancreas graft failure was longer among patients who underwent pancreas retransplantation (7.6 years vs. 4.6 years). Rates of death-censored kidney graft failure at last follow-up were lower among patients who underwent pancreas retransplantation (24% vs. 48%; p = .04). However, given the retrospective nature of the study, selection bias may have influenced the observed outcomes. Patient survival was not significantly different between groups. Among patients who underwent retransplantation, 1-year pancreas graft survival was 84%.

The retrospective observational study by Gasteiger at al (2018) assessed the outcomes of pancreas retransplantation for patients with pancreas graft failure (defined as a return to insulin dependence).²¹ The study evaluated pancreas retransplantations performed between 1997 and 2013 at a single Austrian medical university. Fifty-two pancreas retransplantations were identified, and the median follow-up was 65.0 (range, 0.8 to 174.3) months. At 5 years, the overall patient survival rate was 89%; the survival rate for patients who underwent SPK retransplantation was 90% (18/20), and the survival rate for those who received only a pancreas retransplantation was 88% (28/32). Graft survival rates were 79% at 1 year and 69% at 5 years. The 5-year graft survival rate was higher following SPK retransplantation than pancreas retransplantation alone: 80% for SPK (16/20) versus 63% (20/32) for pancreas alone (p = .226). During the entire follow-up, 42% (22/52) of the grafts were lost. Two factors significantly associated with long-term graft survival were early surgical complications (odds ratio, 3.29; 95% CI, 1.09 to 9.99; p = .035) and acute rejection (odds ratio, 4.49; 95% CI, 1.59 to 12.68; p = .005). The authors note that because pancreas transplantation is not a life-saving operation, the risks and benefits of the procedure must be carefully considered.

The OPTN has reported data on transplants performed between 2008 and 2015.¹² Patient survival rates after repeat PTA were similar to survival rates after primary transplants. For example, the 1-year survival rate was 91.0% (95% CI, 88.7% to 92.8%) after a primary pancreas transplant and 96.4% (95% CI, 92.1% to 98.4% ) after a repeat pancreas transplant. The numbers of patients transplanted were not reported, but OPTN data stated that 668 patients were alive 1 year after primary transplant and 157 after repeat transplants. The 3-year patient survival rate was 87.5% (95% CI, 85.1% to 89.6%) after primary transplants and 91.2% (95% CI, 86.2% to 94.4% ) after repeat transplants. The 5-year patient survival rate was 79.9% (95% CI, 77.4% to 82.2% ) after primary transplants and 83.7% (95% CI, 78.2% to 88.0% ) after repeat transplants. The 1-year graft survival rate was 81.8% (95% CI, 78.9% to 84.3%) after primary pancreas transplant and 77.7% (95% CI, 70.8% to 83.1%) after repeat transplant.

Data are similar for patients receiving SPK transplants, but follow-up data are only available on a small number of patients who had repeat SPK transplants, so estimates of survival rates in this group are imprecise. Three-year patient survival rate was 94.8% (95% CI, 93.9% to 95.5%) after primary SPK transplant and 87.9% (95% CI, 73.4% to 94.8% ) after a repeat SPK transplant. The number of patients living 3 years after transplant was 2871 after a primary combined procedure and 36 after a repeat combined procedure.

Several centers have published outcomes after pancreas retransplantation and generally reported comparable graft and patient survival rates after initial transplants and retransplants.^22,23,24,25 The largest and most recent studies are further described here. Fridell et al. (2015) reported on 441 initial transplants and 20 late transplants.²³ One-year graft survival rates were 92% after initial transplant and 90% after retransplant (p = .48). Similarly, 1-year patient survival rates were 96% after initial transplants and 95% after retransplants (p = .53). However, Rudolph et al. (2015), who assessed the largest number of patients, reported higher graft survival rates, but not patient survival rates, after primary transplant.²⁵ A total of 2,145 pancreas transplants were performed, 415 (19.3%) of which were retransplants. The death-censored graft survival rate at 1 year was 88.2% in initial transplants and 75.0% in retransplants (p < .001). Patient survival rates at 1 year were 91.3% after initial transplants and 88.2% after retransplants (p = .06).

Section Summary: Pancreas Retransplantation
National and international data reported from specific transplant centers have generally reported similar graft and patient survival rates after pancreas retransplantation compared with initial transplantation.

Potential Contraindications
Pancreas Transplant in Human Immunodeficiency Virus-Positive Transplant Recipients
Current OPTN policy permits human immunodeficiency virus (HIV) -positive transplant candidates.²⁶

The American Society of Transplantation (2019) published a guideline on solid organ transplantation in HIV-infected patients.²⁷ For kidney-pancreas transplants, the following criteria for transplantation are suggested:

• Cluster of differentiation 4 count > 200 cells/mL for at least 3 months (insufficient data to recommend for or against transplantation in patients with counts > 100 cells/mL and no history of opportunistic infection)
• Undetectable HIV viral load while receiving antiretroviral therapy
• Documented compliance with a stable antiretroviral therapy regimen
• Absence of active opportunistic infection and malignancy
• Absence of chronic wasting or severe malnutrition
• Appropriate follow-up with providers experienced in HIV management and ready access to immunosuppressive medication therapeutic drug monitoring.

The guideline authors note that patients with a previous history of progressive multifocal leukoencephalopathy, chronic interstitial cryptosporidiosis, primary central nervous system lymphoma, or visceral Kaposi's sarcoma were excluded from studies of solid organ transplantation in HIV-infected patients. Patients with HIV and concomitant controlled hepatitis B infection may be considered for transplant. Caution is recommended in hepatitis C-coinfected patients who have not been initiated on direct acting antiviral therapy.

Age
Recipient age older than 50 years has been considered a relative contraindication for a pancreas transplant. Several analyses of outcomes by patient age group have prompted general agreement among experts that age should not be a contraindication; however, age-related comorbidities must be considered when selecting patients for transplantation.

In the largest study of pancreas outcomes by recipient age, Siskind et al. (2014) assessed data from the UNOS database.²⁸ Investigators included all adults who received SPK or PTA transplants between 1996 and 2012 (N = 20,854). This included 3160 patients between the ages of 50 and 59 years, and 280 patients aged 60 years or older. Overall, Kaplan-Meier survival analysis found statistically significant differences in patient survival (p < .001) and graft survival (p < .001) by age category. Graft survival was lowest in the 18-to-29 age group at 1, 5, and 10 years, which the authors noted might be due to early immunologic graft rejection as a result of more robust immune responses. However, 10- and 15-year graft survival was lowest in the 60 and older age group. Patient survival rates decreased with increasing age, and the differential between survival in older and younger ages increased with longer follow-up intervals. Lower survival rates in patients 50 and older could be due in part to comorbidities at the time of transplantation. Also, as patients age, they are more likely to die from other causes. Still, patient survival rates at 5 and 10 years are relatively high, as shown in Table 1.

Table 1. Patient Survival by Age Group

Years After Transplant	Age 18 to 29, %	Age 30 to 39, %	Age 40 to 49, %	Age 50 to 59, %	Age 60+, %
1 year	95.4	96.0	94.9	93.3	91.0
5 years	86.3	87.8	85.7	81.6	71.4
10 years	73.5	76.8	71.8	61.5	42.5

Adapted from Siskind et al. (2014).²⁸

Among previous studies on pancreas outcomes in older patients, Shah et al. (2013) reviewed data on 405 patients who underwent PTA transplants between 2003 and 2011.²⁹ One-year patient survival was 100% for patients younger than age 30 years, 98% for patients aged 30 to 39 years, 94% for patients aged 40 to 49 years, 95% for patients aged 50 to 59 years, and 93% for patients aged 60 years or older. There was no statistically significant difference in patient survival by age group (p = .38). Findings were similar for 1-year graft survival; there was no statistically significant difference in outcomes by age of transplant recipients (p = .10).

A study by Afaneh et al. (2011) reviewed data on 17 individuals at least 50 years old and 119 individuals younger than 50 years who had a pancreas transplant at a single institution in the U.S.³⁰ The 2 groups had similar rates of surgical complications, acute rejection, and nonsurgical infections. Overall patient survival was similar. Three- and 5-year survival rates were 93% and 90%, respectively, in the younger group, and 92% and 82%, respectively, in the older group. Schenker et al. (2011) compared outcomes in 69 individuals at least 50 years old with 329 individuals younger than 50 years who had received pancreas transplants.³¹ Mean duration of follow-up was 7.7 years. One-, 5-, and 10-year patient and graft survival rates were similar for the groups. For example, the 5-year patient survival rate was 89% in both groups. The 5-year pancreas graft survival rate was 76% in the older group and 72% in the younger group. The authors of both studies, as well as the authors of a commentary accompanying the Schenker et al. (2011) article,³² agreed that individuals age 50 years and older are suitable candidates for pancreas transplantation.

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements
Guidelines or position statements will be considered for inclusion in Supplemental Information if they were issued by, or jointly by, a U.S. professional society, an international society with U.S. representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

Organ Procurement and Transplantation Network
The Organ Procurement and Transplantation Network updated its comprehensive list of transplant-related policies, most recently in June 2023.²⁶

For pancreas registration:

"Each candidate registered on the pancreas waiting list must meet one of the following requirements:

• Be diagnosed with diabetes
• Have pancreatic exocrine insufficiency
• Require the procurement or transplantation of a pancreas as part of a multiple organ transplant for technical reasons."

For combined kidney plus pancreas registration: "Each candidate registered on the kidney-pancreas waiting list must be diagnosed with diabetes or have pancreatic exocrine insufficiency with renal insufficiency."

U.S. Preventive Services Task Force Recommendations
Not applicable

Ongoing and Unpublished Clinical Trials
Some currently ongoing and unpublished trials that might influence this review are listed in Table 2.

Table 2. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
NCT01047865	Recurrence of T1D in Pancreas Transplantation	400	May 2024
NCT01957696	A Prospective, Observational Study in Pancreatic Allograft Recipients: The Effect of Risk Factors, Immunosuppressive Level and the Benefits of Scheduled Biopsies - on Surgical Complications, Rejections and Graft Survival	80	Oct 2028
Unpublished
NCT00238693	Transplant Registry: Patients Who May Require Transplantation and Those Who Have Undergone Transplantation of Liver, Kidney and/or Pancreas	13,767	Aug 2018
NCT03921593	Prospective Longitudinal Observational Study on Insulin Dependent Diabetic Patients Undergoing Any Form of Solid Organ Pancreas Transplantation Aimed to Clarify Quality of Life Changes After Pancreas Transplantation	110	Mar 2022

NCT: national clinical trial.

References:

1. Kandaswamy R, Stock PG, Gustafson SK, et al. OPTN/SRTR 2018 Annual Data Report: Pancreas. Am J Transplant. Jan 2020; 20 Suppl s1: 131-192. PMID 31898415
2. Black CK, Termanini KM, Aguirre O, et al. Solid organ transplantation in the 21 st century. Ann Transl Med. Oct 2018; 6(20): 409. PMID 30498736
3. United Network for Organ Sharing (UNOS). Transplant trends. 2022; https://unos.org/data/transplant-trends/. Accessed July 5, 2023.
4. Gruessner AC, Gruessner RW. Pancreas Transplantation of US and Non-US Cases from 2005 to 2014 as Reported to the United Network for Organ Sharing (UNOS) and the International Pancreas Transplant Registry (IPTR). Rev Diabet Stud. 2016; 13(1): 35-58. PMID 26982345
5. Kandaswamy R, Stock PG, Miller J, et al. OPTN/SRTR 2019 Annual Data Report: Pancreas. Am J Transplant. Feb 2021; 21 Suppl 2: 138-207. PMID 33595197
6. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Pancreas Transplantation. TEC Assessments. 1998;Volume 13, Tab 7.
7. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Pancreas Retransplantation. TEC Assessments. 2001;Volume 16, Tab 23.
8. Parajuli S, Arunachalam A, Swanson KJ, et al. Outcomes after simultaneous kidney-pancreas versus pancreas after kidney transplantation in the current era. Clin Transplant. Dec 2019; 33(12): e13732. PMID 31628870
9. Bazerbachi F, Selzner M, Marquez MA, et al. Pancreas-after-kidney versus synchronous pancreas-kidney transplantation: comparison of intermediate-term results. Transplantation. Feb 15 2013; 95(3): 489-94. PMID 23183776
10. Fridell JA, Mangus RS, Hollinger EF, et al. The case for pancreas after kidney transplantation. Clin Transplant. 2009; 23(4): 447-53. PMID 19453642
11. Kleinclauss F, Fauda M, Sutherland DE, et al. Pancreas after living donor kidney transplants in diabetic patients: impact on long-term kidney graft function. Clin Transplant. 2009; 23(4): 437-46. PMID 19496790
12. Organ Procurement and Transplantation Network (OPTN). National Data. n.d.; https://optn.transplant.hrsa.gov/data/view-data-reports/national-data/. Accessed July 5, 2023.
13. Barlow AD, Saeb-Parsy K, Watson CJE. An analysis of the survival outcomes of simultaneous pancreas and kidney transplantation compared to live donor kidney transplantation in patients with type 1 diabetes: a UK Transplant Registry study. Transpl Int. Sep 2017; 30(9): 884-892. PMID 28319322
14. van Dellen D, Worthington J, Mitu-Pretorian OM, et al. Mortality in diabetes: pancreas transplantation is associated with significant survival benefit. Nephrol Dial Transplant. May 2013; 28(5): 1315-22. PMID 23512107
15. Sampaio MS, Kuo HT, Bunnapradist S. Outcomes of simultaneous pancreas-kidney transplantation in type 2 diabetic recipients. Clin J Am Soc Nephrol. May 2011; 6(5): 1198-206. PMID 21441123
16. Pugliese A, Reijonen HK, Nepom J, et al. Recurrence of autoimmunity in pancreas transplant patients: research update. Diabetes Manag (Lond). Mar 2011; 1(2): 229-238. PMID 21927622
17. Gruessner AC. 2011 update on pancreas transplantation: comprehensive trend analysis of 25,000 cases followed up over the course of twenty-four years at the International Pancreas Transplant Registry (IPTR). Rev Diabet Stud. 2011; 8(1): 6-16. PMID 21720668
18. Boggi U, Baronti W, Amorese G, et al. Treating Type 1 Diabetes by Pancreas Transplant Alone: A Cohort Study on Actual Long-term (10 Years) Efficacy and Safety. Transplantation. Jan 01 2022; 106(1): 147-157. PMID 33909390
19. Scalea JR, Butler CC, Munivenkatappa RB, et al. Pancreas transplant alone as an independent risk factor for the development of renal failure: a retrospective study. Transplantation. Dec 27 2008; 86(12): 1789-94. PMID 19104423
20. Parajuli S, Arunachalam A, Swanson KJ, et al. Pancreas Retransplant After Pancreas Graft Failure in Simultaneous Pancreas-kidney Transplants Is Associated With Better Kidney Graft Survival. Transplant Direct. Aug 2019; 5(8): e473. PMID 31576369
21. Gasteiger S, Cardini B, Göbel G, et al. Outcomes of pancreas retransplantation in patients with pancreas graft failure. Br J Surg. Dec 2018; 105(13): 1816-1824. PMID 30007018
22. Buron F, Thaunat O, Demuylder-Mischler S, et al. Pancreas retransplantation: a second chance for diabetic patients?. Transplantation. Jan 27 2013; 95(2): 347-52. PMID 23222920
23. Fridell JA, Mangus RS, Chen JM, et al. Late pancreas retransplantation. Clin Transplant. Jan 2015; 29(1): 1-8. PMID 25284041
24. Seal J, Selzner M, Laurence J, et al. Outcomes of pancreas retransplantation after simultaneous kidney-pancreas transplantation are comparable to pancreas after kidney transplantation alone. Transplantation. Mar 2015; 99(3): 623-8. PMID 25148379
25. Rudolph EN, Finger EB, Chandolias N, et al. Outcomes of pancreas retransplantation. Transplantation. Feb 2015; 99(2): 367-74. PMID 25594555
26. Organ Procurement and Transplantation Network (OPTN). OPTN Policies. Updated June 29, 2023; https://optn.transplant.hrsa.gov/media/1200/optn_policies.pdf. Accessed July 5, 2023.
27. Blumberg EA, Rogers CC. Solid organ transplantation in the HIV-infected patient: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. Sep 2019; 33(9): e13499. PMID 30773688
28. Siskind E, Maloney C, Akerman M, et al. An analysis of pancreas transplantation outcomes based on age groupings--an update of the UNOS database. Clin Transplant. Sep 2014; 28(9): 990-4. PMID 24954160
29. Shah AP, Mangus RS, Powelson JA, et al. Impact of recipient age on whole organ pancreas transplantation. Clin Transplant. 2013; 27(1): E49-55. PMID 23228216
30. Afaneh C, Rich BS, Aull MJ, et al. Pancreas transplantation: does age increase morbidity?. J Transplant. 2011; 2011: 596801. PMID 21766007
31. Schenker P, Vonend O, Krüger B, et al. Long-term results of pancreas transplantation in patients older than 50 years. Transpl Int. Feb 2011; 24(2): 136-42. PMID 21039944
32. Gruessner AC, Sutherland DE. Access to pancreas transplantation should not be restricted because of age: invited commentary on Schenker et al. Transpl Int. Feb 2011; 24(2): 134-5. PMID 21208293
33. Centers for Medicare & Medicaid Services (CMS). Transplant. 2021; https://www.cms.gov/Medicare/Provider-Enrollment-and-Certification/CertificationandComplianc/Transplant. Accessed July 5, 2023.
34. Centers for Medicare & Medicaid Services (CMS). National Coverage Determination (NCD) for Pancreas Transplants (260.3). 2006; https://www.cms.gov/medicare-coverage-database/details/ncd-details.aspx?ncdid=107&ver=3. Accessed July 5, 2023.

Coding Section

Codes	Number	Description
CPT	48550	Donor pancreatectomy (including cold preservation), with or without duodenal segment for transplantation
	48551	Backbench standard preservation of cadaver donor pancreas allograft prior to transplantation, including dissection of allograft from surrounding tissues, splenectomy, duodenotomy, ligation of bile duct, ligation of mesenteric vessels, and Y-graft arterial anastomoses from iliac artery to superior mesenteric artery and to spleic artery
	48552	Backbench reconstruction of cadaver donor pancrease allograft prior to transplantation, venous anastomosis, each
	48554	Transplantation of pancreatic allograft
ICD-9 Procedure	52.80	Pancreatic transplant, not otherwise specified
	52.81	Reimplantation of pancreatic tissue
	52.82	Hemotransplant of pancreas
	52.83	Heterotransplant of pancreas
ICD-9 Diagnosis	250.11, 250.13, 250.21, 250.23, 250.31 and 250.33	Codes for Type 1 diabetes mellitus with ketoacidosis, hyperosmolarity or other coma
	250.41 and 250.43	Codes for Type 1 diabetes mellitus with renal complications
	250.81 and 250.83	Codes for Type 1 diabetes mellitus with other specified manifestations
	250.91 and 250.93	Codes for Type 1 diabetes mellitus with unspecified complication
	996.86	Complication of transplanted organ; pancreas
HCPCS	S2065	Simultaneous pancreas kidney transplantation
ICD-10-CM (effective 10/01/15)	E10.10-E10.11	Type 1 diabetes mellitus with ketoacidosis, code range
	E10.21-E10.29	Type 1 diabetes mellitus with kidney complications, code range
	E10.641-E10.649	Type 1 diabetes mellitus with hypoglycemia, code range
	E10.69	Type 1 diabetes mellitus other specified complications
	E10.8	Type 1 diabetes mellitus with unspecified complications
	T86.890-T86.899	Complications of other transplanted tissue, code range
	Z90.5	Acquired absence of kidney
ICD-10-PCS (effective 10/01/15)	0FYG0Z0, 0FYG0Z1	Surgical, hepatobiliary system & pancreas, transplantation, open, code by qualifier (allogeneic or syngeneic)
	0FSG0ZZ, 0FSG4ZZ	Surgical, hepatobiliary system & pancreas, reposition, code by approach (open or percutaneous endoscopic)
Type of Service	Surgery
Plance of Service	Inpatient

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

Index
Pancreas After Kidney Transplant
Pancreas/Kidney Transplant
Pancreas Retransplantation
Pancreas Transplant Alone
Transplant, Pancreas
Transplant, Pancreas/Kidney

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

"Current Procedural Terminology © American Medical Association. All Rights Reserved" 

History From 2013 Forward      

12/08/2023	Annual review, no change to policy intent. Updating background, references and rationale.
12/07/2022	Annual review, no change to policy intent. Updating rationale and references.
12/01/2021	Annual review, no change to policy intent. Updating rationale and references.
12/01/2020	Annual review, no change to policy intent. Updating background, regulatory status, rationale and references.
12/02/2019	Annual review, no change to policy intent. Updating background, rationale and references.
12/21/2018	Annual review, no change to policy intent. Updating rationale and references.
12/20/2017	Annual review, no change to policy intent. Updating background, description, rationale and references.
12/05/2016	Annual review, no change to policy intent.
12/07/2015	Annual review, Pancreas transplant is considered INVESTIGATIONAL in all other circumstances. added to policy verbiage, otherwise, no change to policy intent. Updated background, description, rationale and references.
12/04/2014	Annual review, no change to policy intent. Added coding, updating rationale and references.
12/4/2013	Annual review.  Added related policies and benefit application.  Updated description,rationale and references.