Regulating autologous stem cell interventions in Australia: updated review of the direct-to-consumer advertising restrictions.

Objective This paper provides an update and overview of the law governing direct-to-consumer (DTC) advertising of autologous stem cell interventions (ASCIs) in Australia. It follows significant changes to the advertising regulations made in 2018. Methods The paper reviews the three primary sources or 'centres' of law regulating ASCIs in Australia, together with the relevant guidance documents that supplement these sources. It provides analysis of how the post-2018 advertising regulations, contained in the Therapeutic Goods Act 1989 (Cwlth), apply to all 'biologicals', including ASCIs. It demonstrates how these three sources of law interact with one another and outlines the new tiered offence regime that applies to contraventions of these prohibitions. Results The analysis demonstrates that DTC advertising of ASCIs in Australia is strictly controlled, with primary legislation prohibiting the advertising of biologicals altogether. Conclusions The polycentric legal regime regulating biologicals in Australia clearly makes DTC advertising of ASCIs unlawful. Health practitioners who promote ASCIs, either online, in print or in other media forms, may be penalised in different ways and by different authorities. What is known about the topic? Although several analyses have examined the regulation of ASCIs in Australia, no analysis has studied the reforms made in 2018 relating to the advertising of biologicals. As such, this analysis contributes a fresh examination of these relatively recent reforms. What does this paper add? This analysis clarifies the effects of these new advertising regulations, providing clear guidance on the relevant legal provisions for the benefit of health practitioners and health professionals more generally. What are the implications for practitioners? Health practitioners, especially those who offer ASCIs, should be aware that civil and criminal penalties are likely to be imposed on individuals who promote biologicals in Australia by any means.

Ethical, legal, and societal issues and recommendations for controlled and uncontrolled DCD.

This report deals with organ retrieval procedures in both controlled and uncontrolled DCD, looking at the ethical, legal, and psychosocial aspects during the different phases of the process. A recently published report by the UK Donation Ethics Committee (UKDEC) has served as an important reference document to outline the steps in the controlled DCD patient-donor pathway (Academy of Medical Royal Colleges. UK Donation Ethics Committee. An ethical framework for controlled donation after circulatory death. December 2011). For uncontrolled DCD, the UKDEC pathway description was adapted. At the 6th International Conference in Organ Donation held in Paris in 2013, an established expert European Working Group reviewed the UKDEC reports, which were then considered along with the available published literature. Along this pathway, the crucial ethical, legal, and psychosocial aspects have been flagged, and relevant recommendations have been formulated based on a consensus of the working group.

How to increase organ donation: does opting out have a role?

Every country needs to increase the number of deceased organ donors and the potential impact of a change to opting-out legislation remains unproven, despite the apparent association between opting out and higher donor rates. However, the Spanish model--so successful in Spain and many other countries--is not based on a requirement for opting out, and, in the UK, deceased organ donation has increased by 25% in 3 years through implementation of a series of recommendations that have transformed the infrastructure of donation. A major review of opting out concluded that it is not appropriate for the UK at this time.

Impact of the 1998 UK National Allocation Scheme for deceased heartbeating donor kidneys.

INTRODUCTION: National and regional strategies for allocating deceased heartbeating (DHB) donor kidneys to patients awaiting transplant are of great importance and have major implications for patients and healthcare systems. We describe the rationale for the 1998 National Kidney Allocation Scheme (1998 NKAS) and its impact on renal transplantation in the United Kingdom over 5 years. METHODS: The 1998 NKAS was based on three tiers of patients defined by human leukocyte antigen (HLA) mismatch. This involved national allocation of well-matched kidneys in tiers 1 and 2, with regional allocation for less well-matched patients in tier 3. Pediatric patients (younger than 18 years) and regional patients were prioritized in tiers 1 and 2, with a points score based on six factors determining the specific priority order for allocation. RESULTS: The 1998 NKAS allocated approximately half the kidneys from DHB donors to the national transplant list and resulted in significantly improved HLA matching, more than doubling the proportion of transplants that were 000 HLA-A, -B, and -DR mismatched from 7% to 16% for adults. Pediatric patients achieved comparable levels of HLA matching to adult patients for the first time in the United Kingdom through improved access to adult donor organs. The scheme also benefited highly sensitized patients and improved equity with regard to patient blood group, rareness of HLA type, and HLA homozygosity. CONCLUSION: The 1998 NKAS represented a significant advance for the allocation of DHB donor kidneys in the United Kingdom and, while not addressing inequities in access to transplant, it did largely achieve the principal goal of improving HLA matching.

Factors influencing outcome after deceased heart beating donor kidney transplantation in the United Kingdom: an evidence base for a new national kidney allocation policy.

BACKGROUND: Outcomes after deceased heart beating donor kidney transplantation are good, but survival rates vary according to a number of donor-, recipient-, and transplant-related factors. This comprehensive analysis of transplant outcomes was undertaken to inform development of a new Kidney Allocation Scheme. METHODS: A complete case analysis of the outcome of kidney-only transplants in the United Kingdom, 1995 to 2001, was undertaken using Cox regression modeling. Seven thousand three hundred eighty-five (77%) of the 9585 transplants reported to the UK Transplant Registry were primary transplants in adults. Regrafts and pediatric patients (age <18 years) were analyzed separately. Transplant and patient survival over 5 years were investigated in addition to causes of prolonged cold ischemia time (CIT). RESULTS: A variety of factors significantly adversely influenced kidney transplant and patient outcome, including older donor age, older recipient age, waiting time to transplant over 2 years, diabetes, and earlier year of transplant. Human leukocyte antigen mismatch and CIT were significant in analyses of transplant but not in patient outcome, and an increased graft failure rate was also identified in adolescent patients. CIT was prolonged by long-distance kidney exchanges between centers (2 hr) and reallocation of kidneys for alternative patients (7 hr). CONCLUSION: This study identified a number of factors that influence transplant outcome after deceased heart beating donor kidney transplant in the United Kingdom. The findings suggest that the influences of human leukocyte antigen mismatch and CIT are most relevant in considering a revised kidney allocation scheme.

A New UK 2006 National Kidney Allocation Scheme for deceased heart-beating donor kidneys.

INTRODUCTION: In 2004, it was agreed that a new allocation scheme for kidneys from deceased heart-beating donors was required in the United Kingdom to address observed inequities in access to transplant. The 2006 National Kidney Allocation Scheme (2006 NKAS) was developed to meet agreed objectives and preparatory work included a review of the criteria for human leukocyte antigen (HLA) matching and simulation evidence about the effectiveness of alternative schemes. ALGORITHM FOR 2006 NKAS: The 2006 NKAS gives absolute priority to all 000 HLA-A, -B, -DR-mismatched patients and well-matched pediatric patients (<18 years), and then a points score defines priorities for allocation with waiting time being most influential. Points for age and HLA mismatch are linked in a novel approach to ensure well-matched transplants for younger patients while recognizing that HLA matching is less important for older patients as retransplantation is less likely to be required. To improve equity for difficult to match patients, rare HLA specificities were defaulted to more common, related specificities. IMPACT OF 2006 NKAS: After 3 years, the scheme is already making good progress in achieving its objectives, with overall results similar to those observed in the simulations. There has been a significant benefit for patients waiting more than 5 years for transplant. A number of other advantages of the scheme are also apparent with equity of access improving in many respects, including the achievement of equity of access to transplant for HLA-DR homozygous patients, but geographical inequity of access will take a number of years to address fully.

The UK scheme for mandatory continuous monitoring of early transplant outcome in all kidney transplant centers.

Mandatory continuous monitoring of early transplant outcome with centralized oversight was introduced in 2004 for all 23 UK adult kidney transplant units. Risk-adjusted cumulative sum charts are used to assess 30-day graft and patient survival against past performance for each center, and change in transplant center performance is assessed by tabular cumulative sum charts. The monitoring scheme has performed as predicted from simulations used to establish outcome thresholds and has been validated by comparison with 1- and 5-year outcome data for all UK transplant centers. The value and limitations of the scheme are discussed along with changes that may improve its utility as a tool for self-assessment and central oversight.

Early experience of paired living kidney donation in the United kingdom.

BACKGROUND: Paired living kidney donation became possible in the United Kingdom in 2006 after the introduction of a new legal framework for organ donation. A national matching scheme was subsequently established and we report the early United Kingdom experience of paired donation. METHODS: A new national matching algorithm was developed for the introduction of paired donation in the United Kingdom. Initially, all potential two-way exchanges were identified with prioritization according to a points system based on geographical proximity between pairs, calculated human leukocyte antigen antibody reaction frequency (cRF), HLA mismatch of potential transplant, and donor-donor age difference. Three-way exchanges were additionally considered after the first year. RESULTS: The list for paired donation has grown steadily as 3-monthly "matching runs" have been carried out from April 2007, and in July 2008 there were 85 couples registered. Eight paired donor transplants have resulted with a number of identified exchanges unable to proceed. Fewer potential exchanges have been identified than expected due to blood group composition (47 of 85 donors of group A compared with 16 potential recipients [A, AB]) and high levels of cRF (95%-100% in 35% of patients) among listed patients. CONCLUSIONS: Paired donation has been introduced successfully in the United Kingdom, adding to living donor transplant activity. The new national program has yielded fewer transplants than initially anticipated but as the scheme evolves, with the use of altruistic, nondirected donors to start a "chain" of transplants, an increase in the number of successful paired donation transplants is anticipated.

The effect of mycophenolate mofetil and azathioprine dose on renal allograft outcome in the United kingdom.

BACKGROUND: Mycophenolate mofetil (MMF) therapy compared with azathioprine has not led to improved long-term renal allograft outcomes perhaps as MMF dose is limited by tolerability and dose reduction is associated with inferior graft outcome. The consequences, however, of dose reduction of mycophenolate mofetil relative to azathioprine have not been reported. METHOD: We studied dosing patterns of MMF and azathioprine in the first year after transplantation and their impact on graft outcome after renal transplantation between 1999 and 2002 in the United Kingdom. RESULTS: Sixty-two percent of patients were found to be taking less than 2 g of MMF and 45% were taking less than 100 mg of azathioprine at 1 year after transplantation. Graft outcome was comparable in patients receiving 2 g or more of MMF (n=209), 1 to 2 g of MMF (n=267), and 100 mg or more of azathioprine (n=504) at 1 year after transplantation. Less than 1 g of MMF (n=71) and less than 100 mg of azathioprine (n=413) was associated with a 3-fold and 2-fold increased 4.5 year risk-adjusted hazard ratio (HR) of graft failure, respectively, with reduced graft function. Finally, less than 1 g of MMF was not superior to less than 100 mg of azathioprine. CONCLUSION: Azathioprine levels are not routinely measured and long-term results of concentration controlled MMF studies are awaited. Currently, dose is a useful measure of drug exposure. This study suggests that less than 1 g of MMF and less than 100 mg of azathioprine are associated with inferior graft outcome.

Kidney donation and transplantation in the UK from 1998 to 2007.

There are many changes happening in donation and transplantation in the UK and this review provides a baseline against which the success of future developments can be assessed. There has been a decrease in donation after brain death over the 10-year review period, but increases in both donation after cardiac death and living kidney donation. Antibody incompatible transplantation and paired and altruistic donation programmes are starting to have an impact on the number of living donor transplants carried out and are expected to make a more marked impact in the years ahead. A new national Kidney Allocation Scheme for deceased donors after brain death was introduced in 2006 to replace the previous scheme implemented in 1998. The 2006 scheme aims to improve equity of access to transplant and is showing significant benefits for long-waiting patients. To ensure that all UK transplant centres continue to achieve high standards, both within- and across-centre monitoring of graft and patient outcomes is routinely undertaken and reported. The most important factor in increasing organ donation and transplantation in the UK is the government funding that has been provided to develop national organ donation infrastructures. These major changes are expected to have a significant impact on numbers of donors and transplants in the next 5 years.

Pregnancy after organ transplantation: a report from the UK Transplant pregnancy registry.

BACKGROUND: Maternal and fetal complications in pregnancies after renal transplantation have been highlighted in several reports, but information on their main predisposing factors is limited. The U.K. Transplant Pregnancy Registry was established in 1997 to obtain detailed information on pregnancies in female organ transplant recipients across the U.K. METHODS: For each female kidney, liver, or cardiothoracic organ transplant recipient who had had a recent pregnancy, data on maternal and fetal factors and pregnancy outcomes were collected using forms completed by their transplant follow-up and obstetric units. For kidney transplant recipients, the factors that influence pregnancy outcome were studied using logistic regression, and the effect of pregnancy on graft function was analyzed. RESULTS: There were live births in 83%, 69%, and 79% of pregnancies in cardiothoracic organ, liver, and kidney recipients, respectively. In 50% of live births from renal patients, delivery was preterm (<37 weeks), with 83% of the preterm infants delivered via caesarean. Preterm delivery was associated with maternal drug-treated hypertension and impaired renal function. A matched case-control study showed no evidence of increased renal allograft loss after pregnancy. A univariate survival analysis, however, suggested an association between drug-treated hypertension during pregnancy and poorer postpregnancy graft survival. In patients with prepregnancy serum creatinine (SCr) >150 micromol/L, a trend toward increased postpregnancy SCr was identified. CONCLUSIONS: Pregnancy is likely to end in a live birth in a majority of organ transplant recipients. In patients with greater prepregnancy SCr and/or drug-treated hypertension during pregnancy, however, subsequent renal function may be adversely affected.

Renal transplantation in the United Kingdom for patients from ethnic minorities.

BACKGROUND: To investigate any differences in access to transplant and post-transplant outcomes for ethnic minority patients in the United Kingdom, national data on ethnicity of patients on the waiting list, those receiving a transplant, and deceased donors were analyzed. METHODS: Adult patients and donors were included. Ethnic origin was classified as white, Asian, black, or "other." National data were analyzed, and 2001 U.K. National census data were used for comparative purposes. Median waiting times to transplant were obtained from Kaplan-Meier estimates for patients registered 1998-2000. Transplant survival was estimated for patients transplanted from 1998 to 2003. RESULTS: A total of 92% of the U.K. population was white, compared with 77% of waiting list patients, 88% of transplant recipients, and 97% of deceased donors. Median waiting time to transplantation for white patients was 719 days (95% confidence interval 680-758) compared with 1368 (1131-1605) days for Asian patients and 1419 (1165-1673) days for black patients. The degree of human leukocyte antigen matching achieved was inferior for Asian and black patients. There is some evidence of inferior 3-year transplant survival for black patients compared with white and Asian patients (P=0.03). CONCLUSIONS: There are imbalances in the ethnic make up of the waiting list, the donor pool, and renal transplant recipients. There are significant differences in both post-transplant outcomes and time to transplantation between patients of different ethnic origin. Waiting times are influenced by allocation schemes, and the 2006 U.K. National Kidney Allocation Scheme is designed to achieve greater equity of access to transplant for all patients, regardless of geography, blood group, or ethnicity.

Potential for organ donation in the United Kingdom: audit of intensive care records.

OBJECTIVES: To determine the true potential for solid organ donation from deceased heartbeating donors and the reasons for non-donation from potential donors. DESIGN: An audit of all deaths in intensive care units, 1 April 2003 to 31 March 2005. The study was hierarchic, in that information was sought on whether or not brain stem testing was carried out; if so, whether or not organ donation was considered; if so whether or not the next of kin were approached; if so, whether or not consent was given; if so, whether or not organ donation took place. SETTING: 341 intensive care units in 284 hospitals in the United Kingdom. PARTICIPANTS: 46,801 dead patients, leading to 2740 potential heartbeating solid organ donors and 1244 actual donors. MAIN OUTCOME MEASURES: Proportion of potential deceased heartbeating donors considered for organ donation, proportion of families who denied consent, and proportion of potential donors who became organ donors. RESULTS: Over the two years of the study, 41% of the families of potential donors denied consent. The refusal rate for families of potential donors from ethnic minorities was twice that for white potential donors, but the age and sex of the potential donor did not affect the refusal rate. In 15% of families of potential donors there was no record of the next of kin being approached for permission for organ donation. CONCLUSIONS: Intensive care units are extremely good in considering possible organ donation from suitable patients. The biggest obstacle to improving the organ donation rate is the high proportion of relatives who deny consent.

Long-term graft outcome with mycophenolate mofetil and azathioprine: A paired kidney analysis.

BACKGROUND: Randomized controlled trials and U.S. Registry data have demonstrated that mycophenolate mofetil (MMF) reduces acute rejection rates and improves graft survival. We undertook the first paired kidney analysis comparing the effects of MMF and azathioprine on graft outcome in the United Kingdom. METHODS: In all, 238 deceased donors from 1999 to 2002 who donated one kidney to a patient treated with MMF and the other kidney to a patient treated with azathioprine were identified from the national transplant database held by U.K. Transplant. Graft function and rates of change of graft function were compared using multiple linear regression analyses adjusting for covariates on an intention-to-treat basis. Incidence of acute rejection and delayed graft function were studied using logistic regression. Patient and graft survival censored for death were evaluated with Cox regression analyses. RESULTS: The MMF-treated patients exhibited a nonsignificant trend towards improved graft function but with increased rejection rates (44% versus 31%, P < 0.01). Treatment with MMF did not reduce delayed graft function rates. Univariate analysis showed that graft survival was inferior in MMF-treated patients (90% versus 95%, log-rank, P = 0.02) but in multivariate Cox regression models, MMF treatment was not a significant factor. Surprisingly, in the first year 32% of patients achieved daily doses of less than 2 g of MMF compared to 18% of patients who received less than 100 mg of azathioprine (P < 0.01). CONCLUSION: In this real-life study, there was no difference in patient or graft outcome between MMF and azathioprine treated groups despite increased rejection rates in patients receiving MMF therapy.