Primary biliary cholangitis drug evaluation and regulatory approval: Where do we go from here?

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease. The management landscape was transformed 20 years ago with the advent of ursodeoxycholic acid. Up to 40% of patients do not, however, respond adequately to ursodeoxycholic acid and therefore still remain at risk of disease progression to cirrhosis. The introduction of obeticholic acid as a second-line therapy for patients failing ursodeoxycholic acid has improved outcomes for patients with PBC. There remains, however, a need for better treatment for patients at higher risk. The greatest threat facing our efforts to improve treatment in PBC is, paradoxically, the regulatory approval model providing conditional marketing authorization for new drugs based on biochemical markers on the condition that long-term, randomized placebo-controlled outcome trials are performed to confirm efficacy. As demonstrated by the COBALT confirmatory study with obeticholic acid, it is difficult to retain patients in the required follow-on confirmatory placebo-controlled PBC outcome trials when a licensed drug is commercially available. New PBC therapies in development, such as the peroxisome proliferator-activated receptor agonists, face even greater challenges in demonstrating outcome benefit through randomized placebo-controlled studies once following conditional marketing authorization, as there will be even more treatment options available. A recently published EMA Reflection Paper provides some guidance on the regulatory pathway to full approval but fails to recognize the importance of real-world data in providing evidence of outcome benefit in rare diseases. Here we explore the impact of the EMA reflection paper on PBC therapy and offer pragmatic solutions for generating evidence of long-term outcomes through real-world data collection.

Organ Transplants From Deceased Donors With Primary Brain Tumors and Risk of Cancer Transmission.

Importance: Cancer transmission is a known risk for recipients of organ transplants. Many people wait a long time for a suitable transplant; some never receive one. Although patients with brain tumors may donate their organs, opinions vary on the risks involved. Objective: To determine the risk of cancer transmission associated with organ transplants from deceased donors with primary brain tumors. Key secondary objectives were to investigate the association that donor brain tumors have with organ usage and posttransplant survival. Design, Setting, and Participants: This was a cohort study in England and Scotland, conducted from January 1, 2000, to December 31, 2016, with follow-up to December 31, 2020. This study used linked data on deceased donors and solid organ transplant recipients with valid national patient identifier numbers from the UK Transplant Registry, the National Cancer Registration and Analysis Service (England), and the Scottish Cancer Registry. For secondary analyses, comparators were matched on factors that may influence the likelihood of organ usage or transplant failure. Statistical analysis of study data took place from October 1, 2021, to May 31, 2022. Exposures: A history of primary brain tumor in the organ donor, identified from all 3 data sources using disease codes. Main Outcomes and Measures: Transmission of brain tumor from the organ donor into the transplant recipient. Secondary outcomes were organ utilization (ie, transplant of an offered organ) and survival of kidney, liver, heart, and lung transplants and their recipients. Key covariates in donors with brain tumors were tumor grade and treatment history. Results: This study included a total of 282 donors (median [IQR] age, 42 [33-54] years; 154 females [55%]) with primary brain tumors and 887 transplants from them, 778 (88%) of which were analyzed for the primary outcome. There were 262 transplants from donors with high-grade tumors and 494 from donors with prior neurosurgical intervention or radiotherapy. Median (IQR) recipient age was 48 (35-58) years, and 476 (61%) were male. Among 83 posttransplant malignancies (excluding NMSC) that occurred over a median (IQR) of 6 (3-9) years in 79 recipients of transplants from donors with brain tumors, none were of a histological type matching the donor brain tumor. Transplant survival was equivalent to that of matched controls. Kidney, liver, and lung utilization were lower in donors with high-grade brain tumors compared with matched controls. Conclusions and Relevance: Results of this cohort study suggest that the risk of cancer transmission in transplants from deceased donors with primary brain tumors was lower than previously thought, even in the context of donors that are considered as higher risk. Long-term transplant outcomes are favorable. These results suggest that it may be possible to safely expand organ usage from this donor group.

Challenges for the maintaining the microbiological safety of the UK blood supply.

The supply of blood, blood products and components in the UK, as elsewhere, is safe, although there is no cause for complacency. Use of blood, blood products and components is not without risk of morbidity and mortality. Transfusion-transmitted infections (TTIs) continue to occur and may severely affect the health and welfare of recipients. As indicated by recent and current inquiries, public interest in these TTIs is huge. The risk of TTI can be mitigated but not abolished. Measures to reduce risk include screening of donors, testing of donations and, where appropriate, treatment of donations. The introduction of newer screening tests might identify some infectious donations but come at a cost, which could exceed a justifiable limit. Thus, the recognition, detection, reporting and investigation of cases of possible TTIs need to be improved. Recipients of blood should understand that, although transfusion in the UK is safe, it is not free of risk and so should be provided with full information so that properly informed consent can be given.

Transplantation of Organs From DCD and DBD Donors Who Died After Ligature Asphyxiation.

BACKGROUND: The United Kingdom transplant registry data demonstrated similar transplant outcomes for recipients of kidneys from donors who died following ligature asphyxiation and those who received organs from donors dying from other causes. The impact that this donor cause of death has on the outcomes of other solid organ transplant recipients remains uncertain. METHODS: The United Kingdom transplant registry analysis was undertaken to determine transplant outcomes in recipients of lungs, hearts, livers' and pancreases from donors who died following ligature asphyxiation. RESULTS: Between January 01, 2003, and December 31, 2016, 2.7% (n = 521) of all potential United Kingdom donors died following ligature asphyxiation (mostly suicide by hanging). Of these, 416 (79.9%; 197 donation after brain stem death and 219 donation after circulatory death [DCD]) donated an organ for transplantation. These donors provided organs for 574 transplants (66 lung transplants, 75 heart transplants, 279 liver transplants, and 154 pancreas transplants). Patient and graft survival were similar for recipients of both donation after brain stem death and DCD hearts, livers, and pancreases from donors who died following ligature asphyxiation. Unadjusted graft and patient survival were significantly worse for recipients of lungs from DCD donors who died following ligature asphyxiation. This detrimental effect persisted after propensity score matching. CONCLUSIONS: Livers, hearts, and pancreases from donors who die following ligature asphyxiation suffer an additional warm ischemic insult, but this does not negatively impact transplant outcomes. Outcomes for recipients of DCD lungs appear to be significantly worse.

European Society for Organ Transplantation (ESOT) Consensus Statement on Outcome Measures in Liver Transplantation According to Value-Based Health Care.

Liver transplantation is a highly complex, life-saving, treatment for many patients with advanced liver disease. Liver transplantation requires multidisciplinary teams, system-wide adaptations and significant investment, as well as being an expensive treatment. Several metrics have been proposed to monitor processes and outcomes, however these lack patient focus and do not capture all aspects of the process. Most of the reported outcomes do not capture those outcomes that matter to the patients. Adopting the principles of Value-Based Health Care (VBHC), may provide an opportunity to develop those metrics that matter to patients. In this article, we present a Consensus Statement on Outcome Measures in Liver Transplantation following the principles of VBHC, developed by a dedicated panel of experts under the auspices of the European Society of Organ Transplantation (ESOT) Guidelines' Taskforce. The overarching goal is to provide a framework to facilitate the development of outcome measures as an initial step to apply the VMC paradigm to liver transplantation.

Long-term Care of the Adult Liver Transplant Recipient.

While outcomes after liver transplantation have increased over the last two decades, this is primarily as a consequence of a reduction in early deaths and survival of those who survive the first 6 months has not significantly changed. Causes of premature death and graft loss include cardiovascular disease, renal impairment, malignancy and some infections. As the number of transplant recipients increase, care is being given by primary and secondary care clinicians. Management of the well patient is crucially dependent on careful assessment and where appropriate intervention, especially of cardiovascular risk - such as advice about avoidance of weight gain; management of hypertension, hyperlipidaemia and diabetes; and provision of appropriate lifestyle advice. Other interventions include surveillance for de novo malignancies, active management of immunosuppressive regimen with the need to tailor immunosuppression to the individual. Prompt investigation of abnormalities of liver function is essential. Immune-mediated graft damage still occurs but is less common as a cause for graft loss. Adherence is sometimes an issue, especially in teenagers and young adults, and should be considered and support given where needed. Immunisations (avoiding live and attenuated vaccines) should be encouraged. Recurrence of disease remains an issue, and some interventions (such as appropriate use of antiviral therapy for those grafted with viral hepatitis, use of ursodeoxycholic acid for those grafted for primary biliary cholangitis or long-term steroids for those grafted for autoimmune disease) may improve and maintain graft function. Close collaboration between recipient and the attending clinicians in primary, secondary and tertiary care and close attention to modifiable conditions will lead to improved outcomes.

Outcomes of incoming and outgoing second opinions from a UK liver transplant centre.

OBJECTIVE: Second transplant centre opinions (STCOs) for patients declined for liver transplantation are infrequent. We aimed to identify STCOs outcomes from a tertiary transplant centre. DESIGN: Referrals between 2012 and 2020 to Birmingham Unit were reviewed. Incoming: all referrals from out-of-region centres were collated. Outgoing: patients not listed in Birmingham were reviewed to identify referrals for STCOs to the other UK centres (A-F). RESULTS: 2535 patients were assessed for liver transplantation during the study period. Incoming: among 1751 referrals, 23 STCOs (17 unit A, 3 unit B, 1 unit C, 1 unit D and 1 unit E) were provided by Birmingham. Of the STCOs, 13/23 (57%) patients remained unsuitable for transplantation. Therefore, 10/23 (43%) underwent a second liver transplant assessment, of whom five (50%) were still deemed unsuitable, three (30%) listed (one transplanted) and two (20%) died preassessment. Outgoing: among 426 patients not listed, eight (1.8%) patients were referred for STCO (4 unit E, 2 unit B, 1 unit D, 1 unit A). Three (38%) were listed, two (25%) were assessed and declined, two (25%) were unsuitable for assessment and one (12.5%) died while waiting. Combining incoming and outgoing Birmingham STCOs (n=31), six (19%) of STCOs were listed in a second centre. CONCLUSION: Second transplant centre opinions are rare with the majority still deemed unsuitable for liver transplantation. This highlights potential resource implications especially when undergoing a full second formal assessment. A streamlined STCO process with sharing of investigations and use of telemedicine in appropriate patients may allow for greater transparency, quicker decision making and less use of labour-intensive resources.

Consent in organ transplantation: putting legal obligations and guidelines into practice.

Consent in medical practice is a process riddled with layers of complexities. To some extent, this is inevitable given that different medical conditions raise different sets of issues for doctors and patients. Informed consent and risk assessment are highly significant public health issues that have become even more prominent during the course of the Covid-19 pandemic. In this article we identity relevant factors for clinicians to consider when ensuring consent for solid organ transplantation. Consent to undergo solid organ transplantation is more complex than most surgical and other clinical interventions because of the many factors involved, the complexity of the options and the need to balance competing risks. We first out the context in which consent is given by the patient. We then outline the legal principles pertaining to consent in medical practice as it applies in the UK and the implication of recent legal judgments. The third section highlights specific complexities of consent in organ transplantation and identifies relevant factors in determining consent for organ transplantation. The fourth section offers practical recommendations. We propose a novel 'multi-factor approach' to informed consent in transplantation which includes understanding risk, effective communication, and robust review processes. Whilst understanding risk and communication are a given, our suggestion is that including review processes into the consent process is essential. By this we specifically mean identifying and creating room for discretion in decision-making to better ensure that informed consent is given in practice. Discretion implies that health care professionals use their judgement to use the legal judgements as guidance rather than prescriptive. Discretion is further defined by identifying the relevant options and scope of clinical and personal factors in specified transplantation decisions. In particular, we also highlight the need to pay attention to the institutional dimension in the consent process. To that end, our recommendations identify a gap in the current approaches to consent. The identification of areas of discretion in decision-making processes is essential for determining when patients need to be involved. In other words, clinicians and healthcare professionals need to consider carefully when there is room for direction and where there is little or no room for exercising discretion. In sum, our proposed approach is a modest contribution to the on-going debate about consent in medicine.

Prevalence of abnormal liver tests and liver fibrosis among rural adults in low and middle-income country: A cross-sectional study.

Background: Liver disease is the only major chronic disease and mortality is increasing. Earlier detection of liver fibrosis can reduce progression to cirrhosis and hepatocellular carcinoma. Many studies have reported an increased prevalence in liver fibrosis among adults in urban regions but there are few data in physically active rural populations without attributable metabolic risk factors. This aim of this study is to investigate the prevalence of abnormal liver functions tests (LFTs) and liver fibrosis among adults in a rural population. Methods: This cross-sectional study included observations from KMCH-NNCD-II (2017) study (n = 907) from a farming village, Nallampatti, located in South India. We assessed lifestyle (occupation, tobacco use and alcohol consumption using AUDIT-C questionnaire), markers for metabolic diseases (obesity, hypertension, diabetes, hypercholesterolemia), LFTs and markers for hepatitis viruses B and C. 901 participants had transient elastography to assess fibrosis. Participants with abnormal LFTs and significant liver fibrosis (F2-F4) underwent additional liver screening (caeruloplasmin, iron studies and autoimmune hepatitis panel). Multiple logistic regression analyses were performed to understand the association of liver fibrosis with lifestyle and metabolic risk factors after adjustment for co-variates. Findings: Significant liver fibrosis (F2-F4) was observed in 14.4%, and cirrhosis in 0.8%. There was an association of liver fibrosis with abnormal LFTs but no association between alcohol consumption, viral hepatitis, hepatic liver screening and liver fibrosis. Among metabolic risk factors, no association was observed for hypertension and hypercholesterolemia but diabetes [OR - 3.206 (95% CI: 1.792 - 5.736)], obesity [1.987 (1.341 - 2.944)] and metabolic syndrome [2.539 (1.680 - 3.836)] showed association with significant liver fibrosis (F2-F4) after adjustment for confounding factors. Interpretation: Our results suggest that the prevalence of liver fibrosis in rural population is similar to urban counterparts. The association of metabolic risk factors with liver fibrosis in physically active rural population warrants further investigations in future studies. Funding: This study is funded by KMCH Research Foundation, India.

Immunosuppression in gastroenterology and hepatology.

In recent years, the clinician has a more diverse approach to immunosuppression. Now, for many conditions, such as solid organ transplantation or treatment of some autoimmune diseases, the consequences of immunosuppression becomes a greater risk than organ failure from immune-mediated disease. Some of the consequences of immunosuppression can be prevented by prophylaxis, immunisation, surveillance and pharmacological intervention. Infections and malignancy are major causes of morbidity and mortality in the immunosuppressed. Screening for evidence of latent infection and immunisation prior to introduction of immunosuppression (where possible and appropriate) will help reduce the risk of infection. Surveillance for those cancers that are increased in association with immunosuppression (especially skin cancers, melanoma, anal canal, Kaposi, post-transplant lymphoproliferative disease) will allow early detection and intervention and, where appropriate, alteration of agent.

Organ transplants of the future: planning for innovations including xenotransplantation.

The future clinical application of animal-to-human transplantation (xenotransplantation) is of importance to society as a whole. Favourable preclinical data relevant to cell, tissue and solid organ xenotransplants have been obtained from many animal models utilizing genetic engineering and protocols of pathogen-free husbandry. Findings have reached a tipping point, and xenotransplantation of solid organs is approaching clinical evaluation, the process of which now requires close deliberation. Such discussions include considering when there is sufficient evidence from preclinical animal studies to start first-in-human xenotransplantation trials. The present article is based on evidence and opinions formulated by members of the European Society for Organ Transplantation who are involved in the Transplantation Learning Journey project. The article includes a brief overview of preclinical concepts and biology of solid organ xenotransplantation, discusses the selection of candidates for first-in-human studies and considers requirements for study design and conduct. In addition, the paper emphasizes the need for a regulatory framework for xenotransplantation of solid organs and the essential requirement for input from public and patient stakeholders.

The Need for Alternatives to Liver Biopsies: Non-Invasive Analytics and Diagnostics.

Histology remains essential for the diagnosis and management of many disorders affecting the liver. However, the biopsy procedure itself is associated with a low risk of harm to the patient and cost to the health services; samples may not be adequate and are subject to sampling variation. Furthermore, interpretation often depends on the skill of the pathologist. Increasingly, new techniques are becoming available that are altering the indications for liver biopsy. Many diseases of the liver can be diagnosed and managed using serological and radiological techniques; the degree of fibrosis and fat can often be assessed by serological or imaging techniques and the nature of space occupying lesions defined by serology, imaging and use of liquid biopsy. However, these techniques, too, are subject to limitations: sensitivity and specificity is not always adequate for diagnosis or management; some techniques are expensive and often also require expert interpretation. Although there may be less need for liver biopsy today, histology remains the gold standard as well as an essential tool for the diagnosis and management of many conditions, especially where there are multiple pathologies, or where a diagnosis cannot or has not been made by alternative approaches. Until less invasive techniques become more reliable and accessible, liver histology will remain a key investigation.

Basiliximab With Delayed Tacrolimus Improves Short-Term Renal Outcomes Post-Liver Transplantation-a Real-World Experience.

BACKGROUND: Acute kidney injury (AKI) is common after liver transplantation (LT). Induction with interleukin-2 receptor antagonists is often used as a "renal-sparing" strategy. The aim of this study was to assess this approach in a real-world setting in an LT center. METHODS: A retrospective cohort analysis of LTs between 2011 and 2018 was performed to assess the impact of a renal-sparing strategy using basiliximab in conjunction with mycophenolate mofetil and corticosteroids from day 0 post-LT along with delayed introduction of tacrolimus. This was compared with a group receiving tacrolimus, mycophenolate mofetil, and corticosteroids from the outset. RESULTS: The renal-sparing regimen was associated with significantly lower incidence of all-stage AKI at day 7 post-LT (36% vs 55%, P = .006) and less decline in renal function at 3 months (39% vs 57%, P = .01). No further significant differences in renal outcomes were observed at other time points on follow-up to 1 year post-LT. There was no significant difference in the incidence of acute cellular rejection, inpatient length of stay or graft survival. The decision to adopt a renal-sparing regimen was predominantly made on a clinically reactive basis within the first 24 hours post-LT in 77%, and was preordained in 23%. Cost-effectiveness analysis did not find evidence of a significant cost saving when using a renal-sparing strategy. CONCLUSION: This study provides real-world analysis of the use of a renal-sparing immunosuppression regimen in LT. Although improvements in incidence of AKI in the short term were demonstrated, this did not translate to cost savings or improved renal outcomes after 3 months.

Consent for blood transfusion: summary of recommendations from the Advisory Committee for the Safety of Blood, Tissues and Organs (SaBTO).

The Advisory Committee on the Safety of Blood, Tissues and Organs (SaBTO) decided that its 2011 recommendations on consent for blood transfusion needed to be reviewed and revised due to evidence of poor compliance and recent legal guidance on consent. The recommendations are to ensure that patients are informed about and understand the purpose, benefits and potential risks of transfusion, and have an opportunity to discuss their treatment options. They should be incorporated into local practices for all patients.

Trials & Tribulations of Liver Transplantation- are trials now prohibitive without surrogate endpoints?

During the past 5 decades, liver transplantation has moved from its pioneering days where success was measured in days to a point where it is viewed as a routine part of medical care. Despite this progress, there are still significant unmet needs and outstanding questions that need addressing in clinical trials to improve outcomes for patients. The traditional endpoint for trials in liver transplantation has been 1-year patient survival, but with rates now approaching 95%, this endpoint now poses a number of significant financial and logistical barriers to conducting trials because of the large numbers of participants required to demonstrate only an incremental improvement. Here, we suggest the following solutions to this challenge: adoption of validated surrogate endpoints; bigger and better collaborative multiarm, multiphase studies; recognition by funders and institutions that work on larger collaborative research projects is potentially more important than smaller, self-led bodies of work; ringfenced areas of research within trial frameworks where individuals can take a lead; and fair funding structures using both industry and public sector money across national and international borders.

Follow-up of liver transplant recipients.

The number of surviving liver allograft recipients is increasing almost exponentially. The quality and length of life is increasing but most recipients have reduced survival and quality of life compared with healthy matched individuals. Causes of premature death include cardio and cerebrovascular disease, renal failure, graft failure, de novo malignancy and recurrent disease. Follow-up is needed lifelong to ensure graft and patient health and ensure that complications are recognised and treated early. Immunosuppression is kept to the appropriate minimum and prophylactic interventions are given early, such as use of statins and tight control of blood pressure and blood sugar. Recipients will require life-long follow-up, and this is placing an increasing burden on transplant units. Follow-up is best done by close collaboration between the Liver Transplant Unit, the local hospital and primary care team. Involvement of other health care practitioners, such as recipient coordinators, pharmacists, dermatologists and addiction specialists may improve outcomes. Key to successful follow-up are agreed protocols and good communication between the recipients and all relevant health care providers. Use of IT allows for better communication and will support use of video and telephone consultations in selected instances. The most appropriate follow-up will depend on many factors, including logistic and geographic issues, local experience. The provision of well-funded and supported registries at local, national and international levels will allow for improvements in management.