Budget impact of rare diseases: proposal for a theoretical framework based on evidence from Bulgaria.

This study aimed to estimate the impact of rare disease (RD) drugs on Bulgaria's National Health Insurance Fund's (NHIF) total drug budget for 2011-2014. While standard budget impact analysis is usually used in a prospective way, assessing the impact of new health technologies on the health system's sustainability, we adopted a retrospective approach instead. Budget impact was quantified from a NHIF perspective. Descriptive statistics was used to analyse cost details, while dynamics was studied, using chain-linked growth rates (every period preceding the accounting period serves as a base). NHIF costs for RD therapies were expected to increase up to 74.5 million BGN in 2014 (7.8% of NHIF's total pharmaceutical expenditure). Greatest increase in cost per patient and number of patients treated was observed in conditions, for which there were newly approved for funding therapies. While simple cost drivers are well known - number of patients treated and mean cost per patient - in real-world settings these two factors are likely to depend on the availability and accessibility of effective innovative therapies. As RD were historically underdiagnosed, undertreated and underfunded in Bulgaria, improved access to RD drugs will inevitably lead to increasing budget burden for payers. Based on the evidence from this study, we propose a theoretical framework of a budget impact study for RD. First, a retrospective analysis could provide essential health policy insights in terms of impact on accessibility and population health, which are significant benchmarks in shaping funding decisions in healthcare. We suggest an interaction between the classical prospective BIA with the retrospective analysis in order to optimise health policy decision-making. Second, we recommend budget impact studies to focus on RD rather than orphan drugs (OD). In policy context, RD are the public health priority. OD are just one of the tools to address the complex issues of RD. Moreover, OD is a dynamic characteristic and compromises the consistency and comparability of the calculated budget indicators.

EUROPLAN: a project to support the development of national plans on rare diseases in Europe.

BACKGROUND/AIMS: National Plans for Rare Diseases (RDs) are the common denominator of current public health policy concerns on RDs across the EU. With the aim of a better distribution of the available resources, they conjugate the European objective that aims at ensuring that patients with RDs have access to high-quality care - including diagnostics, treatment and rehabilitation - with the national priorities of selecting specific measures for adoption and implementation. METHODS: The European Project for Rare Diseases National Plans Development (EUROPLAN, www.europlanproject.eu) is cofunded by the EU Commission (DG-SANCO) and is coordinated by the Italian National Center for Rare Diseases of the Istituto Superiore di Sanità (ISS). The EUROPLAN goal is to promote the implementation of National Plans or Strategies to tackle RDs and share relevant experiences within countries, linking national efforts, through a common strategy at a European level. In order to fulfill these objectives, EUROPLAN involved health authorities, clinicians, scientists, the European Organisation for Rare Diseases (EURORDIS), and many other patient groups as associated and collaborating partners from several European countries. RESULTS: The project was launched in 2008 and foresaw 2 implementation phases: phase 1 (2008-2011) to build the consensus definition of operational tools (recommendations and indicators), and the ongoing phase 2 (2012-2015), mainly aimed at capacity building with the proactive involvement of multilevel stakeholders. EUROPLAN is facilitating and accelerating the implementation of National Plans in almost all EU and several non-EU Countries. CONCLUSIONS: EUROPLAN is a European and an international process more than a project, and it could be defined as a 'litmus test' demonstrating how the collaboration between institutions and patients' associations can accelerate the process of awareness and development of policies and actions.

Comparable kinetics of myeloablation between fludarabine/full-dose busulfan and fludarabine/melphalan conditioning regimens in allogeneic peripheral blood stem cell transplantation.

Fludarabine was utilized in the conditioning regimen of 30 adult patients undergoing an allogeneic hematopoietic stem cell transplant. In 18 patients it was combined with full-dose busulfan (FluBu) as a myeloablative regimen and in 12 cases with melphalan (FluMel) as a reduced intensity conditioning (RIC) regimen. Patients in the FluBu group were younger than in the FluMel group (P=0.03). Of 30 patients, 24 received peripheral blood stem cells (PBSC) whereas six patients in the FluBu group received bone marrow cells. The hematological toxicity of each regimen was evaluated by analyzing the kinetics of the neutropenia induced by preparative regimens and the time to recovery of the absolute neutrophils count (ANC) and platelets post transplantation. In PBSC transplants, the median day of severe neutropenia (<500 ANC/microl) occurred on day +6 after the FluBu regimen and on day +3 after FluMel (P=ns), whereas both groups had a duration of severe neutropenia of 9 days and a comparable time for ANC and platelet engraftment. Extra-hematological toxicities were also comparable in the two groups. These findings suggest that the hematological and extra-hematological toxicities induced by fludarabine/full-dose i.v. busulfan are similar to those induced by a standard RIC regimen such as fludarabine/melphalan.

Regimen-related toxicity after fludarabine-melphalan conditioning: a prospective study of 31 patients with hematologic malignancies.

A total of 31 consecutive patients with hematologic malignancies who were considered poor candidates for TBI underwent allogeneic stem cell transplantation after conditioning with fludarabine and melphalan. A total of 25 matched sibling recipients received fludarabine 25 mg/m(2) x 5 days and melphalan 70 mg/m(2) x 2 days. For unrelated and haploidentical donor recipients, fludarabine was increased to 30 mg/m(2) and ATG 30 mg/kg x 4 days was added. Graft-versus-host disease prophylaxis consisted of tacrolimus and mini methotrexate. All patients engrafted. Regimen-related toxicity was considerable and included mainly renal, hepatic and mucosal toxicity. There were seven regimen-related-deaths including two VOD, two pulmonary, one renal, one cardiac and one mucosal toxicity. One case of fatal pulmonary toxicity death could be attributed to pre-existing pulmonary damage. Progression-free survival at 12 months was 44% (90% CI: 30-58%) for recipients of HLA-identical sibling transplants and 33% (90% CI: 21-45%) for all patients. In conclusion, the fludarabine-melphalan regimen leads to consistent engraftment. The regimen-related toxicity is considerable and cannot be explained solely by patient selection. Cardiac toxicity is emerging as a unique toxicity of this regimen. Despite toxicity, fludarabine-melphalan has considerable activity and leads to durable remission in a proportion of patients.

Hostile Hartlepool and genteel Guildford: hostility and health in 10 English towns.

Research from the USA suggests that cities with high mortality rates have high levels of hostility. Our aim was to replicate this research in English towns. A telephone questionnaire, based on the Cook-Medley hostility scale, was administered to random samples of adults in 10 English towns: five with high standardized mortality ratios (SMR) and five with low SMRs. The point estimate for the age-sex-weighted mean hostility score of high SMR towns was higher than that of low SMR towns (mean difference 0.2). However, the 95% confidence interval on the estimate included no difference between the two groups (-0.3-0.8). Our study does not confirm beyond doubt the findings of earlier research in the USA.

Safety and outcome after fludarabine-thiotepa-TBI conditioning for allogeneic transplantation: a prospective study of 30 patients with hematologic malignancies.

Fludarabine, thiotepa and total body irradiation (TBI) has been used as conditioning in haplo-identical transplantation. We studied this conditioning regimen in adults undergoing matched sibling transplantation and alternative donor transplantation. A total of 30 consecutive patients underwent matched related, haplo-identical related or matched unrelated donor transplantation with fludarabine, thiotepa and TBI conditioning. All but four had advanced hematologic malignancies. For haplo-identical transplant, ATG was added to the regimen. All patients received peripheral blood stem cells; these were T-cell depleted for 2-antigen or 3-antigen mismatched related transplantation. Additional graft-versus-host disease prophylaxis consisted of tacrolimus and mini-methotrexate. One recipient of haplo-identical transplant failed to engraft; all other evaluable patients had prompt engraftment. Four patients died of regimen-related toxicity. In all, 14 additional patients died of regimen-related causes including four from failure to thrive with persistent thrombocytopenia and four from delayed pulmonary toxicity. Six patients relapsed. Progression-free survival at 12 months was 47% (90% CI: 25-69%) for recipients of HLA-identical sibling transplants and 30% (90% CI: 14-46%) for all patients. Five of six long-term survivors have extensive chronic GVHD. As a result of the delayed complications and a relatively high recurrence rate, we abandoned this regimen.

Low incidence of CMV viremia and disease after allogeneic peripheral blood stem cell transplantation. Role of pretransplant ganciclovir and post-transplant acyclovir.

To establish the incidence of CMV viremia after allogeneic blood stem cell transplantation, we studied 51 consecutive allogeneic peripheral blood stem cell (PBSC) transplant recipients. A total of 12 recipients were at moderate risk for CMV disease and 39 were at high risk. Conditioning regimens varied, but GvHD prophylaxis consisted of tacrolimus and mini-methotrexate in all patients. All patients received prophylactic ganciclovir from admission until day -2 and prophylactic acyclovir from day -1 until day 180 after transplantation. CMV viremia was treated with ganciclovir. Using a PCR-based technique, the cumulative incidence of CMV viremia was 31+/-14% by day 100 and 35+/-14% by day 150. Donor type, CMV risk group, underlying disorder, conditioning regimen, GvHD, and steroid use were not associated with the risk for CMV viremia. No cases of CMV disease occurred. We hypothesize that the low rate of CMV viremia and the absence of CMV disease in this cohort of PBSCT transplant recipients, which contrasts with other reports, may be related to the prophylactic use of high-dose acyclovir and possibly to pretransplant use of ganciclovir.

Fludarabine and melphalan-based conditioning for patients with advanced hematological malignancies relapsing after a previous hematopoietic stem cell transplant.

Severe regimen-related toxicity often complicates second transplant procedures performed in patients with hematological malignancies that have relapsed after an initial hematopoietic stem cell (HSC) transplant. Therefore, we studied the safety and efficacy of a reduced-intensity fludarabine and melphalan based conditioning regimen in 11 patients who had relapsed following an autologous (n = 7) or allogeneic (n = 4) HSC transplant. All patients received allogeneic peripheral blood HSC from either an HLA-identical (n = 7) or an HLA-mismatched (n = 4) relative. Diagnoses included AML (n = 9), ALL (n = 1), or Hodgkin's disease (n = 1). Only one patient was in complete remission at the time of second transplant. The median interval between first transplant and relapse was 163 days (range 58-1885). Recipients of HLA-mismatched transplants received antithymocyte globulin in addition to fludarabine and melphalan as part of the conditioning regimen. All 11 patients received acute GVHD prophylaxis consisting of tacrolimus and methotrexate. Ten of 11 patients achieved hematopoietic engraftment with a median time to absolute neutrophil count >0.5 x 10(9)/l and to platelet count of >20 x 10(9)/l of 14 and 19 days, respectively. All engrafting patients achieved 100% donor chimerism on initial analysis, except for one with persistent leukemia at day +19. Two patients experienced grade 3 regimen-related toxicity, manifesting as acute renal failure. Acute GVHD grades 2-4 occurred in two recipients and chronic GVHD in four. The 100-day mortality from all causes was 36%. Ten of 11 patients (91%) died a median of 140 days (range 9-996) after the second transplant. The causes of death included relapse (n = 5), sepsis (n = 4), and idiopathic pneumonia syndrome (n = 1). One patient with AML survives in remission at 880 days post-transplant. We conclude that fludarabine- and melphalan-based conditioning promotes full donor chimerism, even following HLA-mismatched transplants. However, the regimen may be more beneficial when applied to patients undergoing allogeneic HSC transplantation earlier in their disease course.

Small area variation in hospital admission: random or systematic?

For some conditions hospital admission is mandatory. This should lead to low variability in admission rates and no effect on admission rate of distance from hospital. If admission is discretionary, we would expect high variability in small area admission rates, and a decline in admission rate as travel time to hospital increases. We wanted to see if non-random variability of admission rates, as measured by the systematic coefficient of variation (SCV), and distance decay, as estimated in regression models, were related. We examined variability and travel time dependence of hospital admission for seven conditions in 62 small (mean population 9900) areas of Surrey, England. Age and sex standardized admission ratios (SAR) were calculated, and their dependence on travel time, adjusting for deprivation, were estimated by linear multiple regression adjusted for spatial correlation. Deprivation was measured by Jarman's score, and time by computerized estimates of drive time to the nearest acute hospital. We found an inverse relationship between time to hospital and admission ratio for ischaemic heart disease, bronchopneumonia and chronic bronchitis. Admission ratios for diabetes mellitus and stroke were related to neither deprivation nor time. For these seven conditions there was no simple relationship between SCV and travel time dependence.