A paclitaxel-hyaluronan conjugate (ONCOFID-P-B™) in patients with BCG-unresponsive carcinoma in situ of the bladder: a dynamic assessment of the tumor microenvironment.

BACKGROUND: The intravesical instillation of the paclitaxel-hyaluronan conjugate ONCOFID-P-B™ in patients with bacillus Calmette-Guérin (BCG)-unresponsive bladder carcinoma in situ (CIS; NCT04798703 phase I study), induced 75 and 40% of complete response (CR) after 12 weeks of intensive phase and 12 months of maintenance phase, respectively. The aim of this study was to provide a detailed description of the tumor microenvironment (TME) of ONCOFID-P-B™-treated BCG-unresponsive bladder CIS patients enrolled in the NCT04798703 phase I study, in order to identify predictive biomarkers of response. METHODS: The composition and spatial interactions of tumor-infiltrating immune cells and the expression of the most relevant hyaluronic acid (HA) receptors on cancer cells, were analyzed in biopsies from the 20 patients enrolled in the NCT04798703 phase I study collected before starting ONCOFID-P-B™ therapy (baseline), and after the intensive and the maintenance phases. Clinical data were correlated with cell densities, cell distribution and cell interactions. Associations between immune populations or HA receptors expression and outcome were analyzed using univariate Cox regression and log-rank analysis. RESULTS: In baseline biopsies, patients achieving CR after the intensive phase had a lower density of intra-tumoral CD8+ cytotoxic T lymphocytes (CTL), but also fewer interactions between CTL and macrophages or T-regulatory cells, as compared to non-responders (NR). NR expressed higher levels of the HA receptors CD44v6, ICAM-1 and RHAMM. The intra-tumoral macrophage density was positively correlated with the expression of the pro-metastatic and aggressive variant CD44v6, and the combined score of intra-tumoral macrophage density and CD44v6 expression had an AUC of 0.85 (95% CI 0.68-1.00) for patient response prediction. CONCLUSIONS: The clinical response to ONCOFID-P-B™ in bladder CIS likely relies on several components of the TME, and the combined evaluation of intra-tumoral macrophages density and CD44v6 expression is a potentially new predictive biomarker for patient response. Overall, our data allow to advance a potential rationale for combinatorial treatments targeting the immune infiltrate such as immune checkpoint inhibitors, to make bladder CIS more responsive to ONCOFID-P-B™ treatment.

Modelling the health and economic impacts ofM72/AS01E vaccination and BCG-revaccination: Estimates for South Africa.

BACKGROUND: Tuberculosis remains a major public health problem in South Africa, with an estimated 300,000 cases and 55,000 deaths in 2021. New tuberculosis vaccines could play an important role in reducing this burden. Phase IIb trials have suggested efficacy of the M72/AS01E vaccine candidate and BCG-revaccination. The potential population impact of these vaccines is unknown. METHODS: We used an age-stratified transmission model of tuberculosis, calibrated to epidemiological data from South Africa, to estimate the potential health and economic impact of M72/AS01E vaccination and BCG-revaccination. We simulated M72/AS01E vaccination scenarios over the period 2030-2050 and BCG-revaccination scenarios over the period 2025-2050. We explored a range of product characteristics and delivery strategies. We calculated reductions in tuberculosis cases and deaths and costs and cost-effectiveness from health-system and societal perspectives. FINDINGS: M72/AS01E vaccination may have a larger impact than BCG-revaccination, averting approximately 80% more cases and deaths by 2050. Both vaccines were found to be cost-effective or cost saving (compared to no new vaccine) across a range of vaccine characteristics and delivery strategies from both the health system and societal perspective. The impact of M72/AS01E is dependent on the assumed efficacy of the vaccine in uninfected individuals. Extending BCG-revaccination to HIV-infected individuals on ART increased health impact by approximately 15%, but increased health system costs by approximately 70%. INTERPRETATION: Our results show that M72/AS01E vaccination or BCG-revaccination could be cost-effective in South Africa. However, there is considerable uncertainty in the estimated impact and costs due to uncertainty in vaccine characteristics and the choice of delivery strategy. FUNDING: This work was funded by the Bill & Melinda Gates Foundation (INV-001754). This work used the Cirrus UK National Tier-2 HPC Service at EPCC (https://www.cirrus.ac.uk) funded by the University of Edinburgh and EPSRC (EP/P020267/1).

Is health expenditure on immunisation associated with immunisation coverage in sub-Saharan Africa? A multicountry analysis, 2013-2017.

OBJECTIVES: The designing of contextually tailored sustainable plans to finance the procurement of vaccines and the running of appropriate immunisation programmes are necessary to address the high burden of vaccine-preventable diseases and low immunisation coverage in sub-Saharan Africa (SSA). We sought to estimate the minimum fraction of a country's health budget that should be invested in national immunisation programmes to achieve national immunisation coverage of 80% or greater depending on the context, with and without donors' support. DESIGN: Multicountry analysis of secondary data using retrieved publicly available data from the WHO, Global Alliance for Vaccines and Immunization (GAVI) and World Bank databases. SETTING: Data on 24 SSA countries, between 2013 and 2017. METHODS: We model the variations in immunisation coverage across the different SSA countries using a fractional logit model. Three different generalised linear models were fitted to explore how various explanatory variables accounted for the variability in each of the three different vaccines-measles-containing vaccine (MCV)1, diphtheria, pertussis, tetanus (DPT3) and BCG. RESULTS: We observed an association between current health expenditure (as a percentage of gross domestic product) and immunisation coverage for BCG (OR=1.01, 95% CI: 1.01 to 1.04, p=0.008) and DPT3 (OR=1.01, 95% CI: 1.0 to 1.02, p=0.020) vaccines. However, there was no evidence to indicate that health expenditure on immunisation (as a proportion of current health expenditure) could be a strong predictor of immunisation coverage (DPT, OR 0.96 (95% CI 0.78 to 1.19; p=0.702); BCG, OR 0.91 (0.69 to 1.19; p=0.492); MCV, OR 0.91 (0.69 to 1.19; p=0.482)). We demonstrate in selected countries that to achieve the GAVI target of 80% in the countries with low DPT3 coverage, health expenditure would need to be increased by more than 45%. CONCLUSIONS: There is a need to facilitate the development of strategies that support African countries to increase domestic financing for national immunisation programmes towards achieving 2030 targets for immunisation coverage.

A mixed integer programming model for vaccine pricing within a group purchasing organization.

BACKGROUND: Setting prices for life-saving medical or pharmaceutical products needs to consider multiple factors, e.g., affordability and health outcomes across different populations. When a group of buyers (e.g., countries) combine their purchasing power (e.g., via a group purchasing organization), the average procurement price decreases in the total volume. Decisions about what price to then charge to each member in a group are particularly challenging, considering the disparities in their respective ability and willingness to pay. Tiered pricing can be an effective way to set prices for a group of buyers, but its performance needs to be quantified and evaluated. METHODS: We modeled the decision of setting prices of a medical product (for example, a vaccine) for a group of buyers using a mixed integer programming model, considering the buyers' ability and willingness to pay. The objective is to minimize the unit price disparity adjusted by the buyers' willingness to pay, subject to the constraint that the prices decrease in the buyers' ability to pay. We also developed an analogous subsidy allocation model that applies if the group receives philanthropic donations to support procurement. The models were illustrated with two case studies based on the Bacillus Calmette-Guerin (BCG) vaccine procurement by Gavi, the Vaccine Alliance and Pan American Health Organization, and the performances of uniform, tiered, and differentiated pricing schemes were examined. RESULTS: The adjusted unit price disparity is non-increasing in the number of price tiers allowed. The biggest decrease in the adjusted price disparity occurs when switching to two-tier pricing from uniform pricing. Tiered pricing performs better in the Gavi group compared to the PAHO group, in part because the ability to pay and willingness to pay have a higher degree of rank correlation within the former group of countries. CONCLUSIONS: This work provides a model for price-setting (subsidy allocation) decisions for a group of buyers and provides a quantitative comparison of different pricing schemes. The results of the case studies suggest that the performance of tiered pricing depends on various factors, including the disparities in the ability and willingness to pay across the buyers. FUNDING: This research has been supported in part by the Center for Health and Humanitarian Systems, the William W. George endowment, and the following benefactors at Georgia Tech: Andrea Laliberte, Richard Rick E. and Charlene Zalesky, and Claudia and Paul Raines.

Bacillus Calmette-Guerin (BCG) therapy is safe and effective in non-muscle invasive bladder cancer (NMIBC) patients with immunomodulating conditions.

INTRODUCTION: Bacillus Calmette-Guerin (BCG) is the most effective therapy available to treat high-risk nonmuscle invasive bladder cancer (NMIBC) patients. However, for patients with immunomodulating conditions BCG is a relative contraindication due to efficacy and safety concerns. To our knowledge, no population-level study evaluating the efficacy and safety profile of BCG for immunomodulated patients exists. METHODS: NMIBC patients aged 66 years or older were identified in the Surveillance, Epidemiology, and End Results (SEER) - Medicare database from 1975-2013. All patients completed adequate BCG (at least 5 plus 2 treatments completed within 12 months of diagnosis). Two groups were defined: an immunomodulated population identified by immunomodulating conditions such as solid-organ transplantation, HIV, and autoimmune conditions, and an immunocompetent group. The primary endpoint was 5-year progression-free survival defined as progression to systemic chemotherapy, checkpoint inhibitors, radical or partial cystectomy, metastasis, or cancer-specific death. A safety analysis was performed as a secondary outcome. RESULTS: In a total of 4,277 patients with NMIBC who completed adequate BCG, 606 (14.2%) were immunomodulated. The immunomodulated group was older at diagnosis (P < 0.001), more likely to be female (P < 0.001), more likely to live in a metropolitan area (P < 0.001), and had higher Charlson comorbidity scores (P < 0.001). There were no differences in progression to chemotherapy (P = 0.17), checkpoint inhibitors (P > 0.99), radical cystectomy (P = 0.40), partial cystectomy (P = 0.93), metastasis (P = 0.19), cancer-specific death (P = 0.18) or 5-year total bladder cancer progression (P = 0.30) between the groups. For the safety analysis, rates of disseminated BCG were similar between immunomodulated and immunocompetent patients (0.7% vs. <1.8%, P = 0.51). On multivariable analysis 5-year total bladder cancer progression (HR 1.07 [CI 0.88-1.30]) was similar between the groups. CONCLUSION: Rates of bladder cancer progression and disseminated BCG complications 5-years after BCG therapy were similar regardless of immunomodulation status. These findings suggest that BCG intravesical therapy can be offered to immunomodulated patients with high-risk NMIBC although theoretical infectious complication risks remain.

Double BCG vaccination in a neonate: implications, management and prevention.

Tuberculosis is a common cause of morbidity and mortality especially in low-income and middle-income countries like India. BCG vaccination is recommended for all neonates after birth in areas with a high tuberculosis disease burden. Here, we describe a case where a neonate received two doses of the BCG (Chennai strain) vaccine within a span of 4 days after birth due to a vaccination error. Parents were informed about the event. The infant was managed conservatively and followed up till 12 months of life for any possible complication. There were no serious adverse effects apart from the localised reaction and a double scar on the left arm. Measures to avoid any such error in the future and the need for reporting medication error has been highlighted. Parental concerns are frequent in such scenarios and should be actively addressed.

Impact of COVID-19 on selected essential public health services - lessons learned from a retrospective record review in the Free State, South Africa.

BACKGROUND: In an attempt to discern lessons to improve future pandemic responses, this study measured the effects of the COVID-19 pandemic on essential public health services (EPHSs) related to primary health care (PHC) and outpatient department (OPD) utilisation, antiretroviral treatment (ART) commencement, drug-susceptible tuberculosis (DS-TB) confirmation and treatment commencement, and Bacillus Calmette-Guérin (BCG) coverage, in the Free State province of South Africa during January 2019 to March 2021. METHODS: A pre-post study design comparing EPHS performance between 2019 and 2020/21 was employed. Routinely collected data were analysed. An interrupted time series analysis was used to measure changes in service use and outcomes from January 2019 to March 2021. Median changes were compared using Wilcoxon rank-sum tests. A 5% statistical significance level was considered. RESULTS: Over the study period, the median values for the annual number of PHC visits was 1.80, 55.30% for non-referred OPD visits, 69.40% for ART commencement, 95.10% and 18.70% for DS-TB confirmation and treatment commencement respectively, and 93.70% for BCG coverage. While BCG coverage increased by 5.85% (p = 0.010), significant declines were observed in PHC utilisation (10.53%; p = 0.001), non-referred OPD visits (12.05%; p < 0.001), and ART commencement (9.53%; p = 0.017) rates. Given the importance of PHC in addressing a new pandemic, along with the existing HIV and TB epidemics - as well as the entire quadruple burden of disease - in South Africa, the finding that the PHC utilisation rate statistically significantly decreased in the Free State post-COVID-19 commencement is particularly concerning. CONCLUSIONS: The lessons learned from this retrospective review attest to a measure of resilience in EPHS delivery in the Free State in as far as a significant hike in BCG vaccination over the study period, 2019-2020/21 was observed. As evidenced by a decline in PHC service utilisation and the decreased numbers of new patients commencing ART, we also learned that EPHS delivery in the province was fragile.

Engagement of community health workers to improve immunization coverage through addressing inequities and enhancing data quality and use is a feasible and effective approach: An implementation study in Uganda.

BACKGROUND: Uganda, like many other developing countries, faces the challenges of unreliable estimates for its immunization target population. Strengthening immunization data quality and its use for improving immunization program performance are critical steps toward improving coverage and equity of immunization programs. The goal of this study was to determine the effectiveness of using community health workers (CHWs) to obtain quality and reliable data that can be used for planning and evidence-based response actions. METHODS: An implementation study in which 5 health facilities were stratified and randomized in two groups to (i) receive a package of interventions including monthly health unit immunization data audit meetings, and defaulter tracking and linkage and (ii) to serve as a control group was conducted between July and September 2020. Immunization coverage of infants in both arms was determined by a review of records three months before and after the study interventions. In addition, key informant and in-depth interviews were conducted among facility-based health workers and CHWs respectively, at the endline to explore the feasibility of the interventions. RESULTS: Overall, a total of 2,048 children under one year eligible for immunization were registered in Bukabooli sub-county by CHWs as compared to the estimated district population of 1,889 children representing a moderate variance of 8.4%. The study further showed that it is feasible to use CHWs to track and link defaulters to points of immunization services as more than two-thirds (68%) of the children defaulting returned for catch-up immunization services. At the endline, immunization coverage for the Oral Polio Vaccine third dose; Rotavirus vaccine second dose; Pneumococcal Conjugate Vaccine third dose increased in both the intervention and control health facilities. There was a decrease in coverage for the Measles-Rubella vaccine decreased in the intervention health facilities and a decrease in Bacillus Calmette-Guérin vaccine coverage in the control facilities. Difference in difference analysis demonstrated that the intervention caused a significant 35.1% increase in coverage of Bacillus Calmette-Guérin vaccine (CI 9.00-61.19; p<0.05)). The intervention facilities had a 17.9% increase in DTP3 coverage compared to the control facilities (CI: 1.69-34.1) while for MR, OPV3, and Rota2 antigens, there was no significant effect of the intervention. CONCLUSION: The use of CHWs to obtain reliable population estimates is feasible and can be useful in areas with consistently poor immunization coverage to estimate the target population. Facilitating monthly health unit immunization data audit meetings to identify, track, and link defaulters to immunization services is effective in increasing immunization coverage and equity.

Advancing Patient-Centered Outcomes and Equity in Clinical Trials for BCG-Unresponsive Nonmuscle Invasive Bladder Cancer.

This Viewpoint encourages investigators to move beyond FDA guidance toward patient-centered therapies and health equity for BCG-unresponsive bladder cancer.

New tuberculosis vaccines in India: modelling the potential health and economic impacts of adolescent/adult vaccination with M72/AS01E and BCG-revaccination.

BACKGROUND: India had an estimated 2.9 million tuberculosis cases and 506 thousand deaths in 2021. Novel vaccines effective in adolescents and adults could reduce this burden. M72/AS01E and BCG-revaccination have recently completed phase IIb trials and estimates of their population-level impact are needed. We estimated the potential health and economic impact of M72/AS01E and BCG-revaccination in India and investigated the impact of variation in vaccine characteristics and delivery strategies. METHODS: We developed an age-stratified compartmental tuberculosis transmission model for India calibrated to country-specific epidemiology. We projected baseline epidemiology to 2050 assuming no-new-vaccine introduction, and M72/AS01E and BCG-revaccination scenarios over 2025-2050 exploring uncertainty in product characteristics (vaccine efficacy, mechanism of effect, infection status required for vaccine efficacy, duration of protection) and implementation (achieved vaccine coverage and ages targeted). We estimated reductions in tuberculosis cases and deaths by each scenario compared to the no-new-vaccine baseline, as well as costs and cost-effectiveness from health-system and societal perspectives. RESULTS: M72/AS01E scenarios were predicted to avert 40% more tuberculosis cases and deaths by 2050 compared to BCG-revaccination scenarios. Cost-effectiveness ratios for M72/AS01E vaccines were around seven times higher than BCG-revaccination, but nearly all scenarios were cost-effective. The estimated average incremental cost was US$190 million for M72/AS01E and US$23 million for BCG-revaccination per year. Sources of uncertainty included whether M72/AS01E was efficacious in uninfected individuals at vaccination, and if BCG-revaccination could prevent disease. CONCLUSIONS: M72/AS01E and BCG-revaccination could be impactful and cost-effective in India. However, there is great uncertainty in impact, especially given the unknowns surrounding the mechanism of effect and infection status required for vaccine efficacy. Greater investment in vaccine development and delivery is needed to resolve these unknowns in vaccine product characteristics.

Seasonal influence on respiratory tract infection severity including COVID-19 quantified through Markov Chain modeling.

Respiratory tract infections (RTIs) are a burden to global health, but their characterization is complicated by the influence of seasonality on incidence and severity. The Re-BCG-CoV-19 trial (NCT04379336) assessed BCG (re)vaccination for protection from coronavirus disease 2019 (COVID-19) and recorded 958 RTIs in 574 individuals followed over 1 year. We characterized the probability of RTI occurrence and severity using a Markov model with health scores (HSs) for four states of symptom severity. Covariate analysis on the transition probability between HSs explored the influence of demographics, medical history, severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), or influenza vaccinations, which became available during the trial, SARS-CoV-2 serology, and epidemiology-informed seasonal influence of infection pressure represented as regional COVID-19 pandemic waves, as well as BCG (re)vaccination. The infection pressure reflecting the pandemic waves increased the risk of RTI symptom development, whereas the presence of SARS-CoV-2 antibodies protected against RTI symptom development and increased the probability of symptom relief. Higher probability of symptom relief was also found in participants with African ethnicity and with male biological gender. SARS-CoV-2 or influenza vaccination reduced the probability of transitioning from mild to healthy symptoms. Model diagnostics over calendar-time indicated that COVID-19 cases were under-reported during the first wave by an estimated 2.76-fold. This trial was performed during the initial phase of the COVID-19 pandemic in South Africa and the results reflect that situation. Using this unique clinical dataset of prospectively studied RTIs over the course of 1 year, our Markov Chain model was able to capture risk factors for RTI development and severity, including epidemiology-informed infection pressure.

Underutilization of intravesical chemotherapy and immunotherapy for high grade non-muscle invasive bladder cancer in California between 2006-2018: Effect of race, age and socioeconomic status on treatment disparities.

OBJECTIVE: Among patients diagnosed with non-muscle invasive bladder cancer (NMIBC), those with high risk disease have the greatest risk of recurrence and disease progression. The underutilization of intravesical immunotherapy with Bacillus Calmette-Guérin (BCG) has been a longstanding concern in clinical practice. This study aimed to determine the disparities present in receipt of adjuvant intravesical chemotherapy and immunotherapy in treatment of patients with high grade NMIBC following initial transurethral resection of a bladder tumor (TURBT). METHODS: The California Cancer Registry data was used to identify 19,237 patients diagnosed with high grade NMIBC who underwent TURBT. Treatment variables include re-TURBT, re-TURBT and intravesical chemotherapy (IVC) and/or BCG. Independent variables include age, sex, race/ethnicity, neighborhood socioeconomic status (nSES), primary insurance payer and marital status at diagnosis. Multiple logistic regression and multinomial regression models were used to examine variation in the treatments received following TURBT. RESULTS: The proportion of patients receiving TURBT followed by BCG was similar across all racial and ethnic groups (28%-32%). BCG therapy was higher in patients belonging to the highest nSES quintile (37% for highest vs. 23%-26% for the 2 lowest quintiles). In multiple variable analyses, receipt of any intravesical therapy (IVT) was influenced by nSES, age, marital status, race/ethnicity, and insurance type. Patients in the lowest nSES quintile had a 45% less likelihood of receiving IVT compared to the highest nSES group (OR [95%CI]: 0.55[0.49, 0.61]). Race/ethnicity differences in receipt of any adjuvant therapy were noted in the middle to lowest nSES quintile for Hispanic and Asian/Pacific Islander patients when compared to non-Hispanic White patients. When comparing variation in treatment by insurance type at diagnosis, those with Medicare or other insurance were 24% and 30% less likely to receive BCG after TURBT compared to those with private insurance, (OR [95%CI]: 0.76 [0.70, 0.82] and 0.70[0.62, 0.79]) respectively. CONCLUSION: In patients with a diagnosis of high risk NMIBC, disparities in utilization of BCG are seen based on SES, age, and insurance type.

Non-restrictive open vial policy combined with the home visit vaccinations for improving BCG coverage in a high-incidence outreach region: A model-based cost-effectiveness analysis for Indonesia.

Background: Bacillus Calmette-Guérin (BCG) vaccination is recommended at birth or in the first week of life to achieve the most beneficial effects in protecting against the most severe type of tuberculosis (TB) disease in children. However, delayed vaccination is commonly reported, especially in outreach or rural areas. We assessed the cost-effectiveness of combining non-restrictive open vial and home visit vaccination strategies in order to increase timely BCG vaccination in a high-incidence outreach setting. Methods: We applied a simplified Markov model for the Papua setting, which resembled a high-incidence outreach setting in Indonesia, to assess the cost-effectiveness of these strategies from a health care and a societal perspective. A moderate increase (75% wastage rate and 25% home vaccination) and a large increase (95% wastage rate and 75% home vaccination) scenario were assessed in the analysis. We calculated incremental cost-effectiveness ratios (ICER) based on the incremental costs and quality-adjusted life years (QALYs) gained by comparing the two strategies to the base case scenario (35% wastage rate and no home vaccination). Results: The costs per vaccinated child were US$10.25 in the base case scenario, increasing slightly in the moderate (US$10.54) and large increase scenarios (US$12.38). The moderate increase scenario was predicted to prevent 5783 TB-related deaths and 790 TB cases while the large increase scenario predicted the prevention of 9865 TB-related deaths and 1348 TB cases for the entire lifespan of our cohort. From a health care perspective, the ICERs were predicted to be US$288/QALY and US$487/QALY, respectively, for the moderate and large increase scenarios. Using Indonesia's gross domestic product (GDP) per person as a threshold, both strategies were considered to be cost-effective. Conclusions: We found that the allocation of resources for timely BCG vaccination based on combining home vaccination and a less restrictive open vial strategy could substantially reduce childhood TB cases and TB-related mortality. Although outreach activities are more expensive than vaccination at a health care facility only, these activities proved to be cost-effective. These strategies might also be beneficial in other high-incidence outreach settings.

Assessment of adherence to pre-vaccination precautions and AEFI reporting practices during BCG vaccination in 4 hospitals in Ghana.

The BCG vaccine, like all other vaccines, is associated with adverse events following immunization (AEFI). Reducing the incidence of AEFI is crucial in reposing confidence in BCG vaccination and reducing hesitancy associated with the vaccine. This requires safety precautions before and during vaccinations, as well as reporting AEFIs after vaccination. This study assessed the adherence of health-care professionals to pre-vaccination precautions and adverse events following immunization (AEFI) reporting practices during BCG vaccination in four hospitals in Ghana. It is hoped that the findings of the study will serve as a baseline to identify gaps for further studies to generate a stronger evidence for policy formulation aimed at improving BCG vaccine safety in Ghana and other tuberculosis endemic countries. A cross-sectional study design was employed, and Statistical Package for Social Sciences, IBM® SPSS version 25 (SPSS Inc. USA) software was used for analysis. Chi-square and binary logistic regression tests were used to test the association between categorical variables and predictors of adherence to pre-BCG vaccination precautions, respectively, and a p-value of <.05 was considered statistically significant. The AEFIs commonly reported by mothers included abscess, injection site pain, injection site redness, fever, rash, muscle weakness, diarrhea, vomiting, coughing and rhinitis. Ninety-three participants (73.2%) were adherent to pre-BCG vaccination precautions. Ninety-two participants (72.4%) informed mothers to report all AEFIs encountered. Adherence to pre-BCG vaccination precautions and AEFI reporting were generally good; however, there is still room for improvement.

Sequential intravesical gemcitabine-docetaxel vs. bacillus Calmette-Guerin (BCG) in the treatment of non-muscle invasive bladder cancer: A preliminary cost-effectiveness analysis.

INTRODUCTION: Treatment naïve patients with high-risk non-muscle invasive bladder cancer (NMIBC) are treated with bacillus Calmette-Guérin (BCG) therapy as the standard of care. Recently, intravesical sequential gemcitabine-docetaxel in the BCG-naïve setting was shown to be well-tolerated and effective, raising the possibility of a new first line intravesical therapy. Cost effectiveness of this intervention remains unknown; therefore, we designed a cost effectiveness study evaluating BCG vs. sequential gemcitabine-docetaxel in patients with high risk NMIBC. METHODS: Using TreeAgePro 2019 software, we developed a Markov model to evaluate BCG vs. gemcitabine-docetaxel from the U.S. Medicare perspective with a 2-year time horizon. Model probabilities and utilities were derived from published literature. Direct costs were obtained from Medicare cost databases. Our primary outcomes were effectiveness (measured in quality adjusted life years [QALYs]), cost and the incremental cost-effectiveness ratio with a willingness to pay threshold of $100,000. RESULTS: Our results indicate that while both treatments resulted in similar QALYs of 1.76, the mean costs per patient at 2 years were $12,363 and $7,090 for BCG and gemcitabine-docetaxel, respectively. Therefore, the BCG strategy was dominated by the gemcitabine-docetaxel strategy as it was equally effective and less costly. One way sensitivity analyses were completed and gemcitabine-docetaxel remained a cost-effective strategy. CONCLUSIONS: The findings of this preliminary cost-effectiveness analysis are novel in that they highlight a well tolerated, efficacious drug that is less expensive than the traditional gold standard therapy. In modern medicine, we are more often challenged by agents with marginally increased efficacy but at significantly higher costs; gemcitabine-docetaxel represents a rare entity which is a success for both patients and healthcare systems alike.

Evaluating the cost-utility of intravesical Bacillus Calmette-Guérin versus radical cystectomy in patients with high-risk non-muscle-invasive bladder cancer in the UK.

AIMS: Approximately 75% of bladder cancer (BC) cases present as non-muscle-invasive BC (NMIBC). In patients with high-risk NMIBC, the mainstay treatment is intravesical Bacillus Calmette-Guérin (BCG), with immediate radical cystectomy (RC) as an alternative treatment option. The aim of the present study was to evaluate the cost-utility of BCG versus RC in patients with high-risk NMIBC from the UK healthcare payer perspective. MATERIALS AND METHODS: A six-state Markov model was developed that covered controlled disease, recurrence, progression to muscle-invasive BC, metastatic disease, and death. The model included adverse events of BCG and RC and monitoring and palliative care. Drug costs were obtained from the British National Formulary. Intravesical delivery, RC, and monitoring costs were sourced from the National Tariff Payment System and the literature. Utility data were obtained from the literature. Analyses were run over a 30-year time horizon, with future costs and effects discounted at 3.5% per annum. One-way and probabilistic sensitivity analyses were performed. RESULTS: The base case analysis comparing BCG with RC showed that BCG would increase life expectancy by 0.88 years versus RC, from 7.74 to 8.62 years. BCG resulted in an increase of 0.76 quality-adjusted life years (QALYs) versus RC, from 5.63 to 6.39 QALYs. Patients incurred lower lifetime costs if treated with BCG (£47,753) than with RC (£64,264). Cost savings were mainly driven by the lower cost of BCG versus RC, and palliative care costs. Sensitivity analyses showed that results were robust to assumptions. LIMITATIONS: The evidence base informing efficacy estimates of BCG is heterogeneous as different BCG administration schedules were reported in the literature, while incidence and cost data on some BCG-associated adverse events were sparse. CONCLUSIONS: Intravesical BCG led to increased QALYs and reduced costs versus RC for patients with high-risk NMIBC from the UK healthcare payer perspective.

Intravesical Bacillus Calmette-Guérin (BCG) is a recommended immunotherapy option for patients with high-risk non-muscle invasive bladder cancer (NMIBC) who have undergone transurethral resection of bladder tumor (TURBT). BCG is known for its high efficacy and good safety profile. However, current evidence on its effectiveness against other comparators such as radical cystectomy (RC) is limited, mainly because different BCG schedules are used, particularly with regard to maintenance therapy. Given this lack of evidence, we conducted the first cost-utility analysis which considers adequate BCG therapy relative to RC for the UK. We developed a Markov model that captured the effects of the intravesical BCG and RC on NMIBC, in addition to incidences of adverse events associated with either treatment. Costs of the two treatments, their administration, maintenance, and of treatments for adverse events were modelled alongside the quality-of-life effects of NMIBC, adverse events, and palliative care. We used published clinical data and UK cost data to inform our model. Our results show that BCG was associated with higher quality-adjusted life expectancy than RC and lower total costs from the healthcare system perspective. These results imply that adequate BCG immunotherapy is likely valuable for the National Healthcare System in terms of its effects on patients and indeed cost-saving relative to RC.

Variation in Statewide Intravesical Treatment Rates for Non-Muscle Invasive Bladder Cancer During the Bacillus Calmette-Guerin Drug Shortage.

OBJECTIVE: To measure the changes in treatment patterns for non-muscle invasive bladder cancer before and during the Bacillus Calmette-Guerin (BCG) drug shortage. MATERIALS AND METHODS: We used a 5% random sample of Medicare beneficiaries and identified 7971 bladder cancer patients (2648 pre-BCG shortage and 5323 during the shortage) ≥66 years of age who received intravesical treatment within 1 year of diagnosis between 2010 and 2017. The BCG shortage period was defined from July 2012 ongoing. Full induction treatment with BCG, mitomycin C, gemcitabine, or other intravesical agents was defined as receiving ≥5 of 6 treatments within 60 days. State-level BCG use before and during the drug shortage was compared in US states reporting at least 50 patients in each period. Independent variables included year of index date, age, sex, race, rurality, and region of residence. RESULTS: BCG utilization rates decreased 5.9% in the shortage period (95% CI (-8.2%)-(-3.7%)). The proportion of patients that completed a full induction course of BCG decreased from 31.0% in the pre-shortage period to 27.6% in the shortage period (P = .002). 84% of reporting states (16 of 19) had decreased BCG utilization ranging between 5% and 36% compared to pre-shortage rates. CONCLUSION: During the BCG drug shortage, eligible bladder cancer patients were less likely to receive gold standard intravesical BCG with a large variation in treatment patterns between US states.

Does Therapeutic Repurposing in Cancer Meet the Expectations of Having Drugs at a Lower Price?

Therapeutic repurposing emerged as an alternative to the traditional drug discovery and development model (DDD) of new molecular entities (NMEs). It was anticipated that by being faster, safer, and cheaper, the development would result in lower-cost drugs. As defined in this work, a repurposed cancer drug is one approved by a health regulatory authority against a non-cancer indication that then gains new approval for cancer. With this definition, only three drugs are repurposed for cancer: Bacillus Calmette-Guerin (BCG) vaccine (superficial bladder cancer, thalidomide [multiple myeloma], and propranolol [infantile hemangioma]). Each of these has a different history regarding price and affordability, and it is not yet possible to generalize the impact of drug repurposing on the final price to the patient. However, the development, including the price, does not differ significantly from an NME. For the end consumer, the product's price is unrelated to whether it followed the classical development or repurposing. Economic constraints for clinical development, and drug prescription biases for repurposing drugs, are barriers yet to be overcome. The affordability of cancer drugs is a complex issue that varies from country to country. Many alternatives for having affordable drugs have been put forward, however these measures have thus far failed and are, at best, palliative. There are no immediate solutions to the problem of access to cancer drugs. It is necessary to critically analyze the impact of the current drug development model and be creative in implementing new models that genuinely benefit society.

Cost-Effectiveness of Nadofaragene Firadenovec and Pembrolizumab in Bacillus Calmette-Guérin Immunotherapy Unresponsive Non-Muscle Invasive Bladder Cancer.

OBJECTIVES: Nadofaragene firadenovec is a gene therapy for bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC) undergoing Food and Drug Administration review. Pembrolizumab is approved for treating patients with BCG-unresponsive NMIBC with carcinoma in situ (CIS). We evaluated the cost-effectiveness of these treatments compared with a hypothetical therapeutic alternative, at a willingness-to-pay threshold of $150 000 per quality-adjusted life-year (QALY) gained, in CIS and non-CIS BCG-unresponsive NMIBC populations. METHODS: We developed a Markov cohort simulation model with a 3-month cycle length and lifetime horizon to estimate the total costs, QALYs, and cost per additional QALY from the health sector perspective. Clinical inputs were informed by results of single-arm clinical trials evaluating the treatments, and systematic literature reviews were conducted to obtain other model inputs. Sensitivity analyses were conducted to assess uncertainty in model results. RESULTS: Nadofaragene firadenovec, at a placeholder price 10% higher than the price of pembrolizumab, had an incremental cost-effectiveness ratio of $263 000 and $145 000 per QALY gained in CIS and non-CIS populations, respectively. Pembrolizumab had an incremental cost-effectiveness ratio of $168 000 per QALY gained for CIS. A 5.4% reduction in pembrolizumab's price would make it cost-effective. The model was sensitive to many inputs, especially to the probabilities of disease progression, initial treatment response and durability, and drug price. CONCLUSIONS: The cost-effectiveness of nadofaragene firadenovec will depend upon its price. Pembrolizumab, although not cost-effective in our base-case analysis, is an important alternative in this population with an unmet medical need. Comparative trials of these treatments are warranted to better estimate cost-effectiveness.

Disparities in the prevalence and management of high-risk non-muscle invasive bladder cancer.

OBJECTIVE: To evaluate the associations of socioeconomic characteristics with the management of non-muscle invasive bladder cancer (NMIBC). METHODS: We identified adult patients aged 18 to 89 years with Ta, T1, or Tis NMIBC in the NCDB. We then examined the associations of patient and socioeconomic characteristics with the guidelines-based management of high-risk NMIBC using multivariable logistic regression. RESULTS: 163,949 patients were included in the study cohort, including 64% with Ta, 32% with T1, and 4% with Tis disease. Among those diagnosed with bladder cancer, male (OR 1.24, 95%CI 1.21-1.27), uninsured (OR 1.10, 95%CI 1.01-1.19 vs. private), and non-White (OR 1.34, 95%CI 1.28-1.41 for Black; OR 1.10; 95%CI 1.03-1.18 for Other vs. White) patients were more likely to be diagnosed with high-risk disease, as well as patients from lower education level areas. Among those with high-risk NMIBC, patients who were older, non-White, Hispanic, uninsured or insured with Medicaid were less likely to receive guideline recommended intravesical BCG, while those residing in rural and higher education level areas were more likely to receive BCG. When examining non-guidelines based use of radiotherapy for HGT1 disease, older age (OR 1.06; 95% CI 1.04-1.07) and VA/Military insurance (OR 2.73; 95%CI 1.07, 6.98 vs. private) were associated with radiotherapy use. CONCLUSION: There are strong disparities in the prevalence and management of high-risk NMIBC. These observations highlight important targets for future strategies to reduce such healthcare disparities and provide more equitable bladder cancer treatment to patients.