Improving Waiting Time for Chemotherapy with Ahead-of-Time Drug Preparation.

Waiting time for chemotherapy infusion is a fundamental factor to measure quality of care. It has been shown that a prolonged waiting time is related to a higher incidence of anticipatory nausea and poor patient adherence to scheduled appointments and recommended oncology treatment programs. Some chemotherapy regimens can be prepared hours ahead-of-time, due to long stability. We aimed to study the effect of an informatic-led workflow redesign intervention, facilitating workflow changes in the Oncology Pharmacy, on patient waiting time. This intervention included changes on EHR processes and the chemotherapy CPOE. Their main effect was allowing ahead-of-time preparation of selected chemotherapy regimes. We conducted a cross sectional study, comparing waiting times pre and post intervention periods. A total of 4600 programmed chemotherapy episodes were included. We found a 26.5 % decrease in the mean wait time in the post intervention period (p > 0.02). We were able to show a decrease in waiting time and a measurable impact of the intervention. This evaluation produced valuable and actionable data for Oncology units and adds a valuable, Latin American experience to the literature.

Descentralización de la elaboración de los tratamientos antineoplásicos. Optimización de los recursos / Decentralisation of the preparation of antineoplastic treatments. Resources

Objetivos: La metodología “Six Sigma” se basa en el análisis de los flujos de trabajo e identificación de los puntos de mejoras con el fin de lograr una máxima eficiencia en los procesos, tanto industriales como sanitarios. El objetivo de este estudio es comparar la eficiencia entre un sistema “clásico” de elaboración de quimioterapia centralizado en el Servicio de Farmacia frente a un modelo descentralizado. Material y métodos: Estudio observacional en el que se analizó la eficiencia de los modelos de elaboración de preparaciones quimioterápicas: 1.- Modelo clásico (MC), a partir del cual se suministran las preparaciones al Hospital de Día de Hematología: las campanas de elaboración de tratamientos y el farmacéutico están presentes en el Servicio de Farmacia.2.- Modelo descentralizado (MD): el farmacéutico y las campanas de preparación de la medicación se encuentran en Hospital de Día de Oncología. La eficiencia de cada sistema se evaluó mediante el tiempo transcurrido desde la recepción de la orden médica hasta la administración de la quimioterapia (TAQ).Resultados: El TAQ siguiendo el MD fue inferior que para el MC: 13,7 [5-28] minutos versus 71,0 [42-96] minutos (p<0,001) con una diferencia media de 57,3 minutos/preparación. El tiempo potencialmente ahorrado con el modelo descentralizado fue de 40,3 horas/día. Conclusiones: Con el presente trabajo hemos querido cuantificar y comparar la eficiencia de los dos modelos de elaboración de mezclas citostáticas, siendo desfavorable para el sistema clásico de centralización para la preparación de la medicación en los Servicios de Farmacia. (AU)

Aims: The «Six Sigma» methodology is based on the analysis of workflows and the identification of areas for improvement in order to achieve maximum efficiency in industrial and healthcare processes. The aim of this study is to compare the efficiency of a «classic» chemotherapy preparation system centralised in the Pharmacy Service versus a decentralised model.Material and methods: Observational study in which the efficiency of the models for the preparation of chemotherapy treatments was analysed: 1.- Classical model (MC), which has the treatment preparation cabinets and a pharmacist located in the Pharmacy Service, and from which the preparations are supplied to the Haematology Day Hospital. 2.- Decentralised model (MD), where both the pharmacist and the medication preparation cabinets are located in the Oncology Day Hospital .For the evaluation of the efficiency of each system, the time elapsed from the receipt of the medical order to the administration of chemotherapy (TAQ) was compared. Results: The TAQ following MD was less than for MC: 13.7 [5-28] minutes versus 71.0 [42-96] minutes (p<0.001) with a mean difference of 57.3 minutes/prescription. The potential time saved with the decentralised model was 40.3 hours/day. Conclusions: The aim of this study was to quantify and compare the efficiency of the two models for the preparation of cytostatic mixtures, showing that the classical centralised system for the preparation of medication in pharmacy services is unfavourable. (AU)

A microbial supply chain for production of the anti-cancer drug vinblastine.

Monoterpene indole alkaloids (MIAs) are a diverse family of complex plant secondary metabolites with many medicinal properties, including the essential anti-cancer therapeutics vinblastine and vincristine1. As MIAs are difficult to chemically synthesize, the world's supply chain for vinblastine relies on low-yielding extraction and purification of the precursors vindoline and catharanthine from the plant Catharanthus roseus, which is then followed by simple in vitro chemical coupling and reduction to form vinblastine at an industrial scale2,3. Here, we demonstrate the de novo microbial biosynthesis of vindoline and catharanthine using a highly engineered yeast, and in vitro chemical coupling to vinblastine. The study showcases a very long biosynthetic pathway refactored into a microbial cell factory, including 30 enzymatic steps beyond the yeast native metabolites geranyl pyrophosphate and tryptophan to catharanthine and vindoline. In total, 56 genetic edits were performed, including expression of 34 heterologous genes from plants, as well as deletions, knock-downs and overexpression of ten yeast genes to improve precursor supplies towards de novo production of catharanthine and vindoline, from which semisynthesis to vinblastine occurs. As the vinblastine pathway is one of the longest MIA biosynthetic pathways, this study positions yeast as a scalable platform to produce more than 3,000 natural MIAs and a virtually infinite number of new-to-nature analogues.

False positive results: a challenge for laboratory physicians and hematologists in treating multiple myeloma with daratumumab.

Daratumumab injection was approved by China in 2019 for the treatment of recurrent or refractory multiple myeloma. However, the molecular weight of daratumumab, an immunoglobin G1 kappa human monoclonal antibody, was similar to that of M protein and could not be distinguished from IgG κ M protein in SPEP and SIFE. It might lead to false-positive detection resulting in misdiagnose and confusing evaluation of therapeutic response, especially for patients with IgG κ M proteins. Herein, we reported two cases encountered in our daily clinical work. These two case reports could serve as a reminder to global hematologists who have not yet started or just begun to use the drug of daratumumab.

[Administrative delays of temporary recommendation for use: Impact on access to innovation in melanoma]. / Délais administratifs des RTU, effet sur l'accès à l'innovation dans le mélanome.

INTRODUCTION: Melanoma has benefited in recent years from therapeutic innovations, which have improved overall survival of patients. France has developed a regulatory arsenal allowing faster access to innovative drugs before marketing authorization: temporary authorization for use (ATU) and temporary recommendation for use (RTU). METHOD: We describe here the decision-making processes that led to the non-publication of the decree on the funding of three RTU in adjuvant melanoma therapy: nivolumab, pembrolizumab and the combination of dabrafenib and trametinib, and we analyse the fate of these drugs in order to quantify the potential loss of chance. RESULTS: On 03AUG2018, the French National Agency for Medicines and Health Product Safety (ANSM) published 3 RTU in order to give rapid access to major innovations in adjuvant melanoma therapy: nivolumab, pembrolizumab and the combination of dabrafenib and trametinib. These drugs have respectively demonstrated reductions in the risk of recurrence by 35 %, 43% and 55% for target populations of 2200, 1900 and 650 patients per year. Despite a favourable opinion on reimbursement from the French National Authority for Health (HAS), the decrees on reimbursement will never be published, prohibiting the use of these products before the marketing authorisation, and depriving many patients of a potential cure. CONCLUSION: Despite a favourable opinion from scientists and health agencies for the rapid availability of a drug, the French public health code does not systematically imply access to a therapeutic innovation. The reform of access to innovation implemented on 01JUL2021 may help tackle this issue.

Access to cancer medicines deemed essential by oncologists in 82 countries: an international, cross-sectional survey.

BACKGROUND: The WHO Essential Medicines List (EML) identifies priority medicines that are most important to public health. Over time, the EML has included an increasing number of cancer medicines. We aimed to investigate whether the cancer medicines in the EML are aligned with the priority medicines of frontline oncologists worldwide, and the extent to which these medicines are accessible in routine clinical practice. METHODS: This international, cross-sectional survey was developed by investigators from a range of clinical practice settings across low-income to high-income countries, including members of the WHO Essential Medicines Cancer Working Group. A 28-question electronic survey was developed and disseminated to a global network of oncologists in 89 countries and regions by use of a hierarchical snowball method; each primary contact distributed the survey through their national and regional oncology associations or personal networks. The survey was open from Oct 15 to Dec 7, 2020. Fully qualified physicians who prescribe systemic anticancer therapy to adults were eligible to participate in the survey. The primary question asked respondents to select the ten cancer medicines that would provide the greatest public health benefit to their country; subsequent questions explored availability and cost of cancer medicines. Descriptive statistics were used to compare access to medicines between low-income and lower-middle-income countries, upper-middle-income countries, and high-income countries. FINDINGS: 87 country-level contacts and two regional networks were invited to participate in the survey; 46 (52%) accepted the invitation and distributed the survey. 1697 respondents opened the survey link; 423 were excluded as they did not answer the primary study question and 326 were excluded because of ineligibility. 948 eligible oncologists from 82 countries completed the survey (165 [17%] in low-income and lower-middle-income countries, 165 [17%] in upper-middle-income countries, and 618 [65%] in high-income countries). The most commonly selected medicines were doxorubicin (by 499 [53%] of 948 respondents), cisplatin (by 470 [50%]), paclitaxel (by 423 [45%]), pembrolizumab (by 414 [44%]), trastuzumab (by 402 [42%]), carboplatin (by 390 [41%]), and 5-fluorouracil (by 386 [41%]). Of the 20 most frequently selected high-priority cancer medicines, 19 (95%) are currently on the WHO EML; 12 (60%) were cytotoxic agents and 13 (65%) were granted US Food and Drug Administration regulatory approval before 2000. The proportion of respondents indicating universal availability of each top 20 medication was 9-54% in low-income and lower-middle-income countries, 13-90% in upper-middle-income countries, and 68-94% in high-income countries. The risk of catastrophic expenditure (spending >40% of total consumption net of spending on food) was more common in low-income and lower-middle-income countries, with 13-68% of respondents indicating a substantial risk of catastrophic expenditures for each of the top 20 medications in lower-middle-income countries versus 2-41% of respondents in upper-middle-income countries and 0-9% in high-income countries. INTERPRETATION: These data demonstrate major barriers in access to core cancer medicines worldwide. These findings challenge the feasibility of adding additional expensive cancer medicines to the EML. There is an urgent need for global and country-level policy action to ensure patients with cancer globally have access to high priority medicines. FUNDING: None.

Can recombinant technology address asparaginase Erwinia chrysanthemi shortages?

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Bacterial L-asparaginase has played an important role in ALL treatment for several decades; however, hypersensitivity reactions to Escherichia coli-derived asparaginases often preclude their use. Inability to receive asparaginase due to hypersensitivities is associated with poor patient outcomes. Erwinia chrysanthemi-derived asparaginase (ERW) is an effective, non-cross-reactive treatment option, but is limited in supply. Consequently, alternative asparaginase preparations are needed to ensure asparaginase availability for patients with hypersensitivities. Recombinant technology can potentially address this unmet need by programming cells to produce recombinant asparaginase. JZP-458, a recombinant Erwinia asparaginase derived from a novel Pseudomonas fluorescens expression platform with no immunologic cross-reactivity to E. coli-derived asparaginases, has the same primary amino acid sequence as ERW, with comparable activity based on in vitro measurements. The efficient manufacturing of JZP-458 would provide an additional asparaginase preparation for patients with hypersensitivities.

Comparative study on anticancer drug access times between FDA, EMA and the French temporary authorisation for use program over 13 years.

INTRODUCTION: The cancer incidence continues to rise worldwide. Medical innovation has a major impact on patient survival, but within drug development, it can take more than 10 years to obtain marketing authorisation (MA). The time required for access to therapeutic innovation remains critical, so France has developed a specific expanded access program named ATU, which allows the administration of drugs before the European Medicines Agency (EMA) approval. The purpose of this study is to put in perspective the average time to access antineoplastic drugs worldwide, taking into account ATU, US Food and Drug Administration (FDA) and EMA approvals. METHODS: The ATU system allows the use of a medicine before its MA, under exceptional conditions. All antineoplastic drugs in oncology that have benefited from the ATU system are analysed in terms of tumour site, biomarkers and number of patients who have access to the drug. RESULTS: Between 1st January 2007 and 31st December 2019, 36 of 64 drugs (56.2%) that received MA in oncology were assigned an ATU, to the benefit of 16,927 patients. Thanks to the ATU, 25 of 36 drugs (69.4%) were made available early, on average 203 d (95% CI, 76-330) before FDA approval and on average 428 d (95% CI, 272-583) before EMA approval. Only three of 36 drugs were approved by the EMA before the FDA, and the average time lapse between European MA and FDA approval for these 36 drugs was 216 d (95% CI, 140-293). CONCLUSION: This article demonstrates that the ATU system allows patients to benefit from therapeutic innovations before MA in Europe and USA, with full coverage by the healthcare system.

[The importance of the logistic warehouse in pandemic period: the experience of the USL Umbria 1 (Perugia, Italy) during covid-19.] / L'importanza del magazzino logistico in periodo di pandemia: l'esperienza dell'USL Umbria 1 durante covid-19.

The pandemic period has generated major problems in the pharmacies of hospitals and local health care companies regarding the distribution of drugs to patients undergoing treatment with chronic drugs. This is because the patient, during the lockdown, was forced to leave the house and go several miles away to reach the place where the drug was dispensed. Moreover, very often, the place was placed in covid-19 hospitals, like the one in Perugia, and was also a risk for the patient himself. The logistical organization allows, in addition to the advantages of traceability, efficiency and savings, with the arrival of the drug at home, a very high patient compliance that also translates into greater security in a pandemic period. To the Usl Umbria 1 of Perugia (Italy) has been centralized the activity of warehouse for all the South area that includes three hospitals and four sanitary districts. Such warehouse, through computerized procedure, guarantees the direct distribution with sending of the medicines directly to the district of belonging of the patient. In this way the patient was not forced to make long and risky trips to continue their chronic therapies. Moreover, this logistic warehouse has also allowed to cope with the correct management of many medicinal specialties that have been used against the SARS-CoV-2 virus avoiding their temporary deficiency for patients already on therapy according to the normal therapeutic indications (anti-inflammatory, antiretroviral and immunomodulatory). This paper aims to demonstrate how logistical organization is of vital importance for a National Health System that has to face increasing costs, ensure the traceability of all processes and, last but not least, survive a worldwide pandemic period.

The current state of patient access to new drugs in South Korea under the positive list system: evaluation of the changes since the new review pathways.

Objective: This study aims to provide an up-to-date analysis of the current state of patient access to new drugs in South Korea, focusing on the effect of new review pathways for reimbursement. Methods: We analyzed patients' access to new drugs, listing rate and lead time until listing from marketing authorization. New pathways were defined as 'price negotiation waiver,' 'risk-sharing agreements,' and 'pharmacoeconomic evaluation exemption.' Results: The listing rate for drugs increased after the introduction of the new pathways (93.7% vs. 77.9%, p < 0.001). Before the new pathways, the median lead time for listing was 21.0 months (95% CI: 16.9-25.0), while afterward it was shortened to 10.9 months (95% CI: 10.2-11.7) (p < 0.001). Conclusion: Although it has strengthened national health insurance coverage by positively impacting the rate and lead time, the lead time for the oncology and orphan drugs is substantially longer as compared to other drugs. Expanding the eligibility criteria to include non-life-threatening but rare or intractable diseases, and resolving the system's operational issues are still necessary.

Estimating the effect of optimizing anticancer drug vials on medical costs in Japan based on the data from a cancer hospital.

BACKGROUND: The substantial increase in the use of expensive anticancer drugs has been accompanied by an increase in the amount of disposing residual liquid from drug preparations. Many Western countries, including the United States, have implemented drug vial optimization (DVO) to prevent the waste of anticancer drugs and have reported the reductions in the total drug costs. This study was designed to estimate the expected reduction in spending on anticancer drugs by Japanese cancer hospitals when DVO was implemented instead of individual preparations and to test the effectiveness of this approach. METHODS: We investigated the doses of drugs used and quantity specifications for individually prepared vials for patients who received anticancer drug treatment in December 2017 at the Outpatient Treatment Center of the National Cancer Center Hospital East. Based on these findings, we calculated the total quantity of each drug used on a given day, and the minimum cost for preparation of the number of specified combinations corresponding to the total cost (DVO preparation). Based on the differences in these two costs, we estimated the economic impact of implementing DVO. RESULTS: While the cost for anticancer drugs for the 1-month study period was US$3,305,595 (US$1 = \110) for individual preparations, the estimated cost for DVO preparations was US$3,092,955, equivalent to a reduction of US$212,640. CONCLUSIONS: Based on these study results, implementation of DVO-based preparation of injectable anticancer drugs in Japan in 2017 would have resulted in saving approximately US$460 million. This calculation revealed the need for the Japanese government to modify the methods employed to calculate drug costs in the insurance system and develop policies for the proper and optimal use of medical resources.