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Importance: Both novel and next-in-class cancer drugs have a role in oncology, but the relative development of each is understudied., Objective: To characterize the mechanisms of action of anticancer drugs approved by the US Food and Drug Administration (FDA) between 2009 and 2020, noting how many approvals were based on a new mechanism of action vs next-in-class approvals., Design, Study, and Participants: This cross-sectional study included all anticancer drugs approved by the FDA from January 2009 to December 2020. The mechanism of action of each drug was extracted from FDA labels. Supportive-care treatments were excluded., Exposures: Name of drug approved, date of approval, indication, tumor type, mechanism of action, broad pharmaceutical class, and biological target. Approvals considering all tumor types and each tumor type separately were classified in 3 nonoverlapping categories: new mechanism of action, next in class, or subsequent approval., Main Outcomes and Measures: The number of all approvals each year; the number of approvals based on a new mechanism of action, either by drug (considering all tumor types) or by indication (considering tumor types separately); and the frequency of these numbers over time., Results: Overall, 332 approvals were included. Between 2009 and 2020, there was an increase in the total number of approvals from 8 to 57. We found that 209 approvals (63%) were for a next-in-class indication in a new tumor type (84 [25%]) or a subsequent indication of the same drug in the same tumor type (195 [59%]). When considering each tumor type separately, 123 approvals (37%) were based on a new mechanism of action., Conclusions and Relevance: In this study, approvals based on a new mechanism of action represented a minority of all approvals. Further consideration of incentives for drug development are needed to prioritize novel or highly innovative and transformative anticancer drugs.

Importance: Apatinib is a novel treatment option for chemotherapy-refractory advanced gastric cancer (GC), but it has not been evaluated in patients with locally advanced GC., Objective: To investigate the effectiveness and safety of apatinib combined with S-1 plus oxaliplatin (SOX) as a neoadjuvant treatment for locally advanced GC., Design, Setting, and Participants: This multicenter, prospective, single-group, open-label, phase 2 nonrandomized controlled trial was conducted in 10 centers in southern China. Patients with M0 and either clinical T2 to T4 or N+ disease were enrolled between July 1, 2017, and June 30, 2019. Statistical analysis was performed from December 1, 2019, to January 31, 2020., Interventions: Eligible patients received apatinib (500 mg orally once daily on days 1 to 21 and discontinued in the last cycle) plus SOX (S-1: 40-60 mg orally twice daily on days 1 to 14; oxaliplatin: 130 mg/m2 intravenously on day 1) every 3 weeks for 2 to 5 cycles. A D2 gastrectomy was performed 2 to 4 weeks after the last cycle., Main Outcomes and Measures: The primary end point was R0 resection rate. Secondary end points were the response rate, toxic effects, and surgical outcome., Results: A total of 48 patients (mean [SD] age, 63.2 [8.2] years; 37 men [77.1%]) were enrolled in this study. Forty patients underwent surgery (38 had gastrectomy, and 2 had exploratory laparotomy), with an R0 resection rate of 75.0% (95% CI, 60.4%-86.4%). The radiologic response rate was 75.0%, and T downstaging was observed in 16 of 44 patients (36.4%). The pathological response rate was 54.2% (95% CI, 39.2%-68.6%); moreover, this rate was significantly higher in patients who achieved a radiologic response compared with those who did not (12 [80.0%] vs 1 [20.0%]; P = .03) and in those who had an Eastern Cooperative Oncology Group Performance Status score of 0 (20 [76.9%] vs 10 [45.5%]; P = .03) or had tumors located in the upper one-third of the stomach (16 [61.5%] vs 7 [31.8%]; P = .04). Patients who achieved a pathological response (vs those who did not) had significantly less blood loss (median [range]: 60 [10-200] mL vs 80 [20-300] mL; P = .04) and significantly more lymph nodes harvested (median [range]: 40 [24-67] vs 32 [19-51]; P = .04) during surgery. Postoperative complications were observed in 7 of 38 patients (18.4%). Grade 3 toxic effects occurred in 16 of 48 patients (33.3%), and no grade 4 toxic effects or preoperative deaths were observed., Conclusions and Relevance: This nonrandomized controlled trial found that apatinib combined with SOX was effective and had an acceptable safety profile as a neoadjuvant treatment for locally advanced GC. A large-scale randomized clinical trial may be needed to confirm the findings., Trial Registration: ClinicalTrials.gov Identifier: NCT03192735.

Introduction: Access to childhood cancer medicines is a critical global health challenge. There is a lack of sufficient context-specific data in Ghana on access to essential medicines for treating childhood cancers. Here, we present an analysis of essential cancer medicine availability, pricing, and affordability using the pediatric oncology unit of a tertiary hospital as the reference point., Method: Data on prices and availability of 20 strength-specific essential cancer medicines and eight non-cancer medicines were evaluated using the modified World Health Organization (WHO)/Health Action International method. Two pharmacies in the hospital and four private pharmacies around the hospital were surveyed. We assessed their median price ratio using the WHO international reference price guide. The number of days wages per the government daily wage salary was used to calculate the affordability of medicines., Results: The mean availability of essential cancer medicines and non-cancer medicines at the hospital pharmacies were 27 and 38% respectively, and 75 and 84% respectively for private pharmacies. The median price ratio of cancer medicines was 1.85, and non-cancer medicines was 3.75. The estimated cost of medicines for treating a 30 kg child with Acute lymphoblastic leukaemia was GHȻ 4928.04 (US$907.56) and GHȻ 4878.00 (US$902.62) for Retinoblastoma, requiring 417 and 413-days wages respectively for the lowest-paid unskilled worker in Ghana., Conclusion: The mean availability of cancer medicines at the public and private pharmacies were less than the WHO target of 80%. The median price ratio for cancer and non-cancer medicines was less than 4, yet the cost of medicines appears unaffordable in the local setting. A review of policies and the establishment of price control could improve availability and reduce medicines prices for the low-income population.

Importance: Several studies have estimated the financial inputs for successful drug development. Such analyses do not capture the large investment that patient study participants commit to drug development., Objective: To estimate the volume of patients required to achieve a first US Food and Drug Administration (FDA) approval for a new anticancer drug or biologic therapy., Design, Setting, and Participants: This cohort study included a random sample of prelicense oncology drugs and biologics with a trial site in the United States that were launched into clinical efficacy testing between January 1, 2006, and December 31, 2010. Drugs and biologics were identified using ClinicalTrials.gov registration records. Total patient enrollment was captured over an 8-year span, and each intervention was classified based on whether it received FDA approval and was deemed as having intermediate or substantial value according to the American Society of Clinical Oncology Value Framework (ASCO-VF) score. Secondarily, the association between patient numbers and intervention characteristics was tested. Data were analyzed in February 2020., Main Outcomes and Measure: The prespecified primary outcome was the number of patients enrolled in prelicense trials per FDA approval., Results: A total of 120 drugs and biologics were included in our study, with 84 (70.0%) targeted agents, 20 (16.7%) immunotherapies, and 71 (59.2%) novel agents. A total of 13 drugs and biologics (10.8%; 95% CI, 5.3%-16.8%) in our sample gained FDA approval within 8 years, of which 1 (7.7%) was deemed of intermediate value and 3 (23.1%) were deemed of substantial value using ASCO-VF scoring. Overall, 158 810 patients were enrolled in 1335 trials testing these drugs and biologics, 47 913 (30.2%) in trials that led to FDA approval and 110 897 (69.8%) in trials that did not. An estimated 12 217 (95% CI, 7970-22 215) patient study participants contributed to prelicense trials per FDA approval. The estimated number of patients needed to produce a single FDA-approved drug or biologic of intermediate or substantial ASCO-VF clinical value was 39 703 (95% CI, 19 391-177 991)., Conclusions and Relevance: The results of this cohort study make visible the substantial patient investment required for prelicense oncology drug development. Such analyses can be used to devise policies that maximize the clinical impact of research on a per-patient basis.

Background: The Fragility Indexquantifies the reliability of positive trials by estimating the number of events, which would change statistically significant results to non-significant results., Methods: We identified randomized trials supporting drug approvals by the US FDA between 2009 and 2019 in lung, breast, prostate, and colon cancers and in melanoma. We reconstructed survival tablesand calculated the number of events, which would result in a non-significant result for the primary endpoint. The FI was then compared to the number of patients in each trial who withdrew consent or were lost to follow-up. Regression analyses were used to explore associations between RCT characteristics and FI and trials in which FI was lower or equal to number of participants who withdrew consent or were lost to follow-up., Results: Among 81 RCTs, the median FI was 28. The median number of patients who withdrew consent or were lost to follow up was 27. FI was equal or lower than the number of patients who withdrew consent or were lost to follow-up in 47 trials (58%). There was a modest increase in FI over time (p = 0.02). Trials with overall survival as the primary endpoint (p = 0.006) and those in the palliative setting (p < 0.001) had lower FI. There was no association with trial sample size or duration of follow-up., Findings: Statistical significance of RCTs in common solid tumours can be reversed often with a small number of additional events. Post-approval RCTs or real-world data analyses should be performed to ensure results of registration trials are robust., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objectives: Real-world evidence (RWE) has gained increased attention in recent years as a complement to traditional clinical trials. The use of RWE to establish the efficacy of oncology drugs for Food and Drug Administration (FDA) approval has not been described. In this paper, we review 5 recent examples where RWE was submitted in support of the FDA approvals of original or supplementary indications for oncology drugs., Methods: To identify cases where RWE was used, we reviewed drug approval packages available at Drugs@FDA for oncology drugs approved between 2017 and 2019. Five cases were selected to present a broad overview of different types of RWE, different circumstances under which RWE has been used for regulatory approvals, and how FDA evaluated the data in each case. The type of RWE submitted, the indication, limitations identified by FDA reviewers, and the outcome of the submission are discussed., Results: RWE, particularly historical controls for rare or orphan indications, has been used to support both original and supplementary oncology drug approvals. Types of RWE included data from electronic health records, claims, post-marketing safety reports, retrospective medical record reviews, and expanded access studies. Small sample sizes, data quality, and methodological issues were among concerns cited by FDA reviewers., Conclusion: By bridging the gap between the constraints of the trial setting and the realities of clinical practice, RWE can add value to a regulatory submission. These early examples provide insight into how regulators evaluated RWE submitted as evidence of efficacy for oncology drugs., (Copyright © 2020 ISPOR–The Professional Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

Purpose: UNC Medical Center converted to an electronic health record (EHR) in 2014. This conversion allowed for the transition of paper chemotherapy orders to be managed electronically. This article describes the process for converting inpatient paper chemotherapy orders into the new EHR in a safe and effective manner., Summary: A collaborative interdisciplinary approach to the EHR transition enabled our organization to move from using paper chemotherapy orders to fully electronic chemotherapy treatment plans in both ambulatory and acute care areas. Active chemotherapy orders for acute care inpatients were reviewed and transcribed by two oncology pharmacists in the cancer hospital prior to being signed by an attending physician. The newly input orders were independently verified by two pharmacists in the cancer hospital inpatient pharmacy. Nurse review of the signed and verified treatment plans, along with reconciliation of the medication administration record ensured a safe transition to the new EHR workflow. Providers benefit from the ability to review treatment plans remotely, track changes, and include supportive medications in one consolidated location. The coordinated team effort allowed for a smooth transition with minimal interruptions to patient care., Conclusion: The pharmacist-led, multidisciplinary conversion to electronic chemotherapy orders was safe, accurate, and occurred ahead of schedule for the EHR go-live. Advance communication and planning around scheduled inpatient admissions helped to minimize the impact of the transition from paper to electronic treatment plans. Both pharmacist and physician engagement were necessary to ensure a smooth transition for active inpatient treatment plans., (© American Society of Health-System Pharmacists 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Cutaneous melanoma is one of the most aggressive forms of skin neoplasms and represents a major cause of neoplastic or cancer death in Europe. Without adequate therapy, the 5-year survival rate is 15% when the disease metastasizes to distant organs. The objective of our study was to evaluate the status quo of the current treatment standards in stage IV melanoma and rationale for therapy decisions in Germany and Austria between January 2016 and September 2018., Methods: In this retrospective, anonymized registry, data of male and female patients with unresectable advanced/metastatic BRAF-positive cutaneous melanoma treated in the first, second, and third line with registered substances were analyzed using descriptive statistics., Results: Ninety-nine patients (50.5% male) received a total of 172 treatment lines. The first (99 patients), second (56 patients), and third (17 patients) treatment lines were documented. Within the 80.8% of patients with stage IV melanoma, targeted therapy (TT) was more frequently administered as a first-line treatment than immunotherapy (IO) with checkpoint inhibitors (59.6% TT vs. 40.4% IO). Across all lines, patients received TT in 54.7% and IO in 43.0% of the cases. As targeted agents, dabrafenib plus trametinib was predominantly prescribed (72.3%), whereas the monotherapy with anti-programmed cell death protein 1 and anti-cytotoxic T lymphocyte-associated protein 4 antibodies or their combination was prescribed similarly often (50.0% vs. 47.3%). Most commonly, the treatment type was switched from TT to IO or vice versa upon disease progression. The most frequent rationales for prescribing either TT or IO were remission pressure (72.9%) or physician's preference (45.0%), respectively. Disease progression was a more frequent cause of treatment discontinuation than undesired events., Conclusion: Patients in Germany and Austria with unresectable advanced or metastatic BRAF-mutant melanoma predominantly receive guideline-recommended treatments. TT was more frequently administered than IO while the rationale for prescribing a specific treatment type differed between the two.

Purpose: To design and implement a chemotherapy stewardship process to optimize the location of chemotherapy administration in an effort to decrease the number of inappropriate inpatient anticancer regimen administrations and decrease institutional costs associated with inpatient administration., Summary: As the costs of anticancer agents continue to rise, it is crucial that multidisciplinary efforts are aimed at managing anticancer medication utilization; this is especially important for high-cost medications, medications whose use requires increased monitoring due to safety concerns, and medications that do not exert effects quickly and, as such, can be more appropriately administered in the outpatient setting. It is imperative that pharmacists play a role in managing chemotherapy medication utilization, as pharmacists provide expertise in formulary management, a vast knowledge of financial impact and reimbursement processes, and clinical knowledge that can help predict the expected effectiveness and adverse effects of each anticancer regimen. Our institution sought to develop and implement a multidisciplinary chemotherapy stewardship program targeting the optimization of site of anticancer agent administration with a goal of decreasing both cost and inappropriate utilization of high-cost, high-risk anticancer agents., Conclusion: Implementation of a chemotherapy stewardship service may decrease the number of inappropriate inpatient anticancer regimen administrations and decrease inpatient resource use, thereby decreasing costs to institutions. The concept of a chemotherapy stewardship process was well received by multidisciplinary healthcare colleagues, and a collaborative approach should be used to design and implement such processes., (© American Society of Health-System Pharmacists 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The therapeutic effect of regorafenib was previously demonstrated in patients with advanced hepatocellular carcinoma (HCC) and Child-Pugh classification A (CP-A) whose disease progressed during sorafenib treatment in a phase III trial. However, treatment options are limited for patients with advanced HCC other than CP-A. In this study, we aimed to evaluate the therapeutic effect of regorafenib on advanced HCC patients including those with Child-Pugh classification B (CP-B).We retrospectively analyzed the medical records of 21 patients with advanced HCC who were treated with regorafenib after sorafenib monotherapy at our hospital from July 2017 to April 2018 and were followed up until September 2019. Patients were classified according to liver function and adverse events experienced during sorafenib treatment and were started on regorafenib with a pre-defined reduced starting dose along with a dose reduction and schedule change based on the judgement of the attending physician.At regorafenib initiation, 13 and 8 patients were classified as CP-A and CP-B, respectively. In all patients with CP-B, the starting dose of regorafenib was reduced, and the pre-defined starting-dose sets were applied to 17 (81%) patients. The median duration of regorafenib treatment in patients with CP-A and CP-B were 4.1 months and 2.0 months, respectively, with no significant difference. The median overall survival from regorafenib initiation (OS-r) and sorafenib initiation (OS-s) was 13.2 months and 30.9 months, respectively. In subgroup analysis, OS-r was 16.3 months in patients with CP-A and 10.1 months with CP-B with no significant difference (P = .44), whereas OS-r was 16.3 months in patients with modified albumin-bilirubin Grade 1/2a and 13.2 months in patients with Grade 2b, with no significant difference. There was no clear difference in the incidence rate of ≥grade 3 adverse events between CP-A and CP-B. OS-r and OS-s were significantly correlated.Even patients with impaired liver function achieved the desired therapeutic effects by safely reducing the starting dose of regorafenib according to both impaired liver function and adverse events during pretreatment. Regorafenib may be considered to be an effective treatment after sorafenib monotherapy in patients with impaired liver function.

Background: The purpose of the current meta-analysis was to compare the oncological outcomes of pemetrexed versus gefitinib in pre-treated advanced or metastatic non-small cell lung cancer (NSCLC) patients., Methods: Search the online electronic databases on comparison the effectiveness and adverse effects of pemetrexed versus gefitinib in therapy outcomes of pre-treated NSCLC to September 2019. All studies analyzed the summary odds ratios (ORs) of the main outcomes, including survival efficacy and toxicity complications., Results: In all, 5 trials involving 676 subjects were included, with 332 receiving pemetrexed and 344 using gefitinib. The pooled analysis of overall survival (OS) (OR = 0.97, 95%CI = 0.77-1.21, P = .76) and progression-free survival (PFS) (OR = 1.17, 95%CI = 0.60-2.30, P = .65) showed that pemetrexed did not achieve benefit when compared with gefitinib. In the results of subgroup analysis among the EGFR mutation-positive patients, the comparison of gefitinib therapy versus pemetrexed did show PFS benefit 0.35 (95%CI 0.12-1.01; P = .05). In terms of grade 3 or 4 side effects, a similar toxicity profile of both pemetrexed and gefitinib was shown in the incidence rate of rash (P = .045), fatigue (P = .97), thrombocytopenia (P = .68) and anemia (P = .21) between the 2 groups., Conclusion: Pemetrexed was not associated with survival benefit than gefitinib therapy among pre-treated NSCLC patients. While, gefitinib showed superior PFS efficacy than pemetrexed for patients with EGFR mutation-type. Future investigations are required to identify relevant biomarkers in selected patients that would most likely benefit from pemetrexed or gefitinib treatment in pre-treated advanced NSCLC patients.

Introduction: Chemotherapies are handled using Good Manufacturing Practices, which ensure asepsis and high-quality production. Continuous education is compulsory and usually includes theoretical and practical exercises., Objectives: This work aimed to validate an innovative method of teaching good manufacturing practices based on an escape room mixing simulation and gaming., Method: Pairs of learners were locked in a simulated clean room (Esclean Room) and had 1 hour to produce a chemotherapy and escape by finding solutions to 23 "Good Manufacturing Practices mysteries" linked to combination locks. To measure the experiment's impact on teaching, questionnaires including the 23 mysteries (in different orders) were filled in before, just after and one month after escape from the Esclean Room. Pharmacy staff' degrees of certainty were noted for each question. A satisfaction survey was completed., Results: Seventy-two learners (29% senior pharmacists, 14% junior pharmacists, and 57% pharmacy technicians) escaped the Esclean Room and 56 answered every questionnaire. The educational intervention resulted in increases in correct answers and certainty. Correct answers rose from 57% in the first questionnaire to 80% in the third ( p  < 0.001). Certainty scores rose from 50% before the experiment to 70% one month afterwards ( p  < 0.001). Despite 68% of learners having never taken part in an escape room game before, 79% liked this educational method., Conclusion: This study built and tested a pedagogical escape room involving a high risk, professional, pharmacy process. The use of this pharmacy technology simulation had a positive impact on pharmacy staff theoretical knowledge.

The field of chemical modification of proteins has been dominated by random modification of lysines or more site-specific labeling of cysteines, each with attendant challenges. Recently, we have developed oxaziridine chemistry for highly selective modification of methionine called redox-activated chemical tagging (ReACT) but have not broadly tested the molecular parameters for efficient and stable protein modification. Here we systematically scanned methionines throughout one of the most popular antibody scaffolds, trastuzumab, used for antibody engineering and drug conjugation. We tested the expression, reactivities, and stabilities of 123 single engineered methionines distributed over the surface of the antibody when reacted with oxaziridine. We found uniformly high expression for these mutants and excellent reaction efficiencies with a panel of oxaziridines. Remarkably, the stability to hydrolysis of the sulfimide varied more than 10-fold depending on temperature and the site of the engineered methionine. Interestingly, the most stable and reactive sites were those that were partially buried, presumably because of their reduced access to water. There was also a 10-fold variation in stability depending on the nature of the oxaziridine, which was determined to be inversely correlated with the electrophilic nature of the sulfimide. Importantly, the stabilities of the best analogs were sufficient to support their use as antibody drug conjugates and potent in a breast cancer mouse xenograft model over a month. These studies provide key parameters for broad application of ReACT for efficient, stable, and site-specific antibody and protein bioconjugation to native or engineered methionines., Competing Interests: Competing interest statement: S.K.E., H.L.T., J.A.W., and the Regents of the University of California have filed a patent application (US Provisional Patent Application UCSF073P) related to engineered methionine mutants on antibody scaffolds.

Purpose of Review: We provide an overview of the current landscape of drug development relevant to childhood cancers. We present recent and ongoing efforts to identify therapeutic targets in pediatric cancers. We describe efforts to improve the approach to clinical trials and highlight the role regulatory changes and multistakeholder platforms play in advancing pediatric cancer drug development., Recent Findings: Expanding knowledge of the genetic landscape of pediatric malignancies through clinical genomics studies has yielded an increasing number of potential targets for intervention. In parallel, new therapies for children with cancer have shifted from cytotoxic agents to targeted therapy, with examples of striking activity in patients with tumors driven by oncogenic kinase fusions. Innovative trial designs and recent governmental policies provide opportunities for accelerating development of targeted therapies in pediatric oncology., Summary: Novel treatment strategies in pediatric oncology increasingly utilize molecularly targeted agents either as monotherapy or in combination with conventional cytotoxic agents. The interplay between new target identification, efforts to improve clinical trial design and new government regulations relevant to pediatric cancer drug development has the potential to advance novel agents into frontline care of children with cancer.

The potential benefits of early patient access to new medicines in areas of high unmet medical need are recognised, but uncertainties concerning effectiveness, safety and added value when new medicines are authorised, and subsequently funded based on initial preliminary data only, have important implications. In 2016 olaratumab received accelerated conditional approval from both the European Medicines Agency and the US Food and Drug Administration for the treatment of soft-tissue sarcoma, based on the claims of a substantial reduction in the risk of death with an 11.8-month improvement in median overall survival in a phase II trial in combination with doxorubicin vs. doxorubicin alone. The failure to confirm these benefits in the post-authorisation pivotal trial has highlighted key concerns regarding early access and conditional approvals for new medicines. Concerns include potentially considerable clinical and economic costs, so that patients may have received suboptimal treatment and any money spent has foregone the opportunity to improve access to effective treatments. As a result, it seems reasonable to reconsider current marketing authorisation models and approaches. Potential pathways forward include closer collaboration between regulators, pharmaceutical companies and payers to enhance the generation of rapid and comparative confirmatory trials in a safe and fair manner, with minimal patient exposure as required to achieve robust evidence. Additionally, it may be time to review early access systems, and to explore new avenues regarding who should pay or part pay for new treatments whilst information is being collected as part of any obligations for conditional marketing authorisation. Greater co-operation between countries regarding the collection of data in routine clinical care, and further research on post-marketing data analysis and interpretation, may also contribute to improved appraisal and continued access to new innovative cancer treatments.

Hazardous drug is a common term used by the National Institute of Occupational Health and Safety (NIOSH) to classify medications that may induce adverse mutagenic and reproductive responses in health care personnel. NIOSH publishes a list of drugs it defines as hazardous where it may be appropriate for health care workers to take protective measures to reduce the potential for occupational exposure. Recent updates and proposed updates to this list have included large molecule biological products with oncology indications. Both NIOSH and USP <800> recommend the use of closed system transfer devices (CSTDs) during compounding. CSTDs are required for administration of prepared solution in NIOSH. However, USP has suggested that the principles of <800> are broadly applicable to hazardous drug handling activities across all facility types. USP encourages the widespread adoption and use of <800> across all health care settings, which many health care workers have interpreted beyond compounding to include administration and preparation of conventionally manufactured sterile products per approved labeling. Although the use of CSTDs may reduce exposure of health care personnel to chemotherapy agents in health care setting, the impact of CSTDs on quality of biologic drug products, including monoclonal antibodies and other proteins, is not fully understood. To complicate this issue further, there are several commercially available CSTDs in the market which have different fluid paths and material of construction that comes in contact with the drug. Testing every combination of CSTD and drug product for potential incompatibilities can be a labor intensive and impractical approach and cause delay in getting essential drugs to patients. A panel discussion was held at a recent American Association of Pharmaceutical Scientists 2018 PharmSci 360 conference to discuss the impact of CSTDs on biologics. Impact on subvisible and visible particulates and impact to other product quality attributes such as high molecular weight species formation upon contact with CSTDs were reported in American Association of Pharmaceutical Scientists meeting. Impact to deliverable dose, holdup volumes of various CSTDs, and stopper coring were also reported that has significant impact to patient safety. Given the fact that USP chapter <800> will be implemented in December 2019, feedback from health authorities regarding the use of CSTDs for biological drug products is needed to provide an appropriate risk/benefit balance to ensure patient safety and quality of the biologic drug product while also protecting the health care worker and the environment. The purpose of this commentary is to provide an industry perspective on the challenges during the use of CSTDs for biologic drug products and is intended to raise caution and awareness on the benefits and shortcomings of these devices., (Copyright © 2020 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Safety concerns have existed for more than 40 years about how hazardous drug (HD) exposure contributes to adverse health outcomes in health care workers. Careless handling causes toxic HD residues to infiltrate hospital and ambulatory care settings and can even be tracked to patient homes. Little is known about the adverse health outcomes experienced by exposed caregivers. The December 1, 2019, release of new regulations will enforce health care organizations to minimize risk to all health care workers by implementing the US Pharmacopeia (USP) General Chapter<800>Hazardous Drugs-Handling in Healthcare Settings safety standards. Worker safety measures include wearing personal protective equipment, even in home care settings.

Medicine is the main means to reduce cancer mortality. However, some medicines face various risks during transportation and storage due to the particularity of medicines, which must be kept at a low temperature to ensure their quality. In this regard, it is of great significance to evaluate and select drug cold chain logistics suppliers from different perspectives to ensure the quality of medicines and reduce the risks of transportation and storage. To solve such a multiple criteria decision-making (MCDM) problem, this paper proposes an integrated model based on the combination of the SWARA (stepwise weight assessment ratio analysis) and CoCoSo (combined compromise solution) methods under the probabilistic linguistic environment. An adjustment coefficient is introduced to the SWARA method to derive criteria weights, and an improved CoCoSo method is proposed to determine the ranking of alternatives. The two methods are extended to the probabilistic linguistic environment to enhance the applicability of the two methods. A case study on the selection of drug cold chain logistics suppliers is presented to demonstrate the applicability of the proposed integrated MCDM model. The advantages of the proposed methods are highlighted through comparative analyses.

Chemotherapy checking is a complex task and requires a high level of alertness and attention to detail. Learning tools are required to teach the fundamental principles of chemotherapy checking. In conjunction with a graphic design team and with input from Human Factors specialists, an online chemotherapy checking training module was created. A variety of learning methods were incorporated including pre-reading, hands on training, case scenarios, and exam questions. The necessary skills to safely complete chemotherapy checking can be enhanced by the use of this training module.

Over the course of the last two decades, there has been a decrease in the incidence of head and neck cancers thanks to a decreasing prevalence of smoking. However, a new risk factor has been coming to the fore: human papillomavirus infection (HPV). HPV-positive oropharyngeal squamous cell carcinoma (HPV+OPC) is more sensitive to chemotherapy and radiotherapy, which translates to a much better prognosis with conventional treatment protocols than tumours that are HPV-negative. Traditional therapeutic interventions are associated with substantial morbidity and have a great impact on patient quality of life. The main focus is on identifying an ideal group of HPV-positive patients who could receive de-intensification treatment regimens aimed at avoiding the late toxicity of treatment. Various strategies are considered, such as reduction in radiotherapy dose following induction chemotherapy, radiotherapy alone, minimally invasive surgical techniques, and substituting platinum-based chemotherapy. The first generation of de-escalation randomised phase III trials have now been published. The following review summarizes the current knowledge and treatment of oropharyngeal carcinoma.

Objective: The purpose of this study was to assess the change in student confidence to perform oncology pharmacy competencies before and after completing oncology didactic instruction using a flipped classroom approach., Methods: First year doctor of pharmacy students completed a survey prior to the Applied Science and Therapeutics (AST) oncology module (pre-survey) and the same survey following the completion of the oncology module (post-survey). The survey consisted of questions addressing prior oncology pharmacy experience related to employment (research or patient care) and education, level of interest in oncology pharmacy, and level of confidence to perform thirteen oncology pharmacy competencies., Results: One-hundred sixteen students completed the pre-survey and 35 completed the post-survey. Students completing both surveys reported greater confidence in all oncology pharmacy competencies (p < 0.0001) after instruction. The greatest increases in student confidence were related to chemotherapy dose calculations, patient education, and drug-drug interactions., Conclusions: The delivery of oncology content using flipped classroom instruction in the AST course successfully increased student confidence in ability to perform oncology pharmacy competencies. Cancer screening, cancer risk factors, and the preparation and dispensing of chemotherapy were competencies identified as needing greater emphasis in classroom instruction. Future studies are needed to assess student's knowledge and application of oncology pharmacy competencies in both the experiential and classroom settings., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background and Objectives : BTK and BCL2 inhibitors have changed the treatment paradigms of high-risk and elderly patients with chronic lymphocytic leukemia (CLL), but their long-term efficacy and toxicity are still unknown and the costs are considerable. Our previous data showed that Rituximab (Rtx) and high-dose methylprednisolone (HDMP) can be an effective and safe treatment option for relapsed high-risk CLL patients. Materials and Methods : We explored the efficacy and safety of a higher Rtx dose in combination with a shorter (3-day) schedule of HDMP in relapsed elderly or unfit CLL patients. Results : Twenty-five patients were included in the phase-two, single-arm trial. The median progression free survival (PFS) was 11 months (range 10-12). Median OS was 68 (range 47-89) months. Adverse events (AE) were mainly grade I-II° (77%) and no deaths occurred during the treatment period. Conclusions : 3-day HDMP and Rtx was associated with clinically meaningful improvement in most patients. The median PFS in 3-day and 5-day HDMP studies was similar and the toxicity of the 3-day HDMP schedule proved to be lower. The HDMP and Rtx combination can still be applied in some relapsed high-risk and elderly or unfit CLL patients if new targeted therapies are contraindicated or unavailable. (ClinicalTrials.gov identifier: NCT01576588)., Competing Interests: R.P., L.G.: research support from Roche Lietuva was achieved (study drug Rituximab was provided by Roche Lietuva) V.V., M.S., J.S., R.M., A.J., T.Z. have no conflicts-of-interest to disclose.

The medication information needs of patients with cancer have been primarily studied using quantitative methods and little qualitative research on this topic exists. The purpose of this study was to explore patients' perspectives of optimal oncology medication education provided to patients at the Nova Scotia Health Authority (NSHA). Adult (≥ 18 years) outpatients in medical, gynecological and hematology oncology at NSHA were invited to participate in focus groups, which were audio-recorded, transcribed and analyzed thematically. Three focus groups, including 21 outpatients, were conducted. Four major themes were identified: (1) preparing for what lies ahead consisted of: readiness to receive information, anxiety over the unknown, setting expectations and patients supporting one another; (2) bridging the information gaps was made up of gap in provision of patient education, gap in continuity of patient education, and gap in trustworthy information; (3) understanding the education needs of the patients was comprised of sources of information, education timing and setting, prioritizing information needs, and individuality; and (4) experience within the health care system encompassed: interactions with health care professionals, willingness to ask questions, patient satisfaction, and financial implications. This study identified previously unknown patient education needs and also supported ideas reported in the literature. This data will guide the strategies that will be used to optimize the delivery of oncology medication education at our facility and other health care institutions.

Background: Dose banding parenteral chemotherapy has the potential to optimise aseptic unit capacity and reduce drug expenditure without compromising the service provided., Methods: Dose banding tables from NHS England were implemented into the electronic chemotherapy prescribing system. Compliance to the dose bands was analysed and submitted quarterly. Analysis of drug expenditure, drug use and cost per milligram data was also collected., Results: Expenditure on the 17 drugs identified in the 2016/17 dose standardisation CQUIN reduced by approximately £100,000 per month over the CQUIN despite an increase in the number of prescribed doses of these drugs. At the beginning of the year, the percentage of work compounded in house was 60%, which was reduced to 51% of total workload at the end of the year due to outsourcing commonly prescribed doses from commercial pharmaceutical aseptic manufacturers., Conclusion: Dose banding parenteral chemotherapy is an efficient cost-saving strategy which also can help to increase the capacity of the aseptic unit.

Background: Successful first-generation drugs can be converted with small alterations to "second-generation drugs," which are cheaper to develop and may pose less financial risk for manufacturers due to already validated action mechanism and a well-defined consumer market., Methods: We found four classes of cancer drugs for first- and second generation products approved in the US: BCR-ABL tyrosine kinase inhibitors (TKI) for treatment of CML, ALK + TKI for NSCLC, CD20 monoclonal antibodies for CLL, and HER2 monoclonal antibodies for breast cancer. We analyzed the characteristics of the clinical trials and the approval pathways for these 14 drugs., Results: First-generation and 4 out of 5 s-generation BCR-ABL TKI drugs were granted expedited approval, while all drugs were approved based on single-arm trials. Both ALK + TKI drugs were based on single-arm trials and expedited approval. The first-generation CD20 monoclonal antibody drug was approved based on single-arm trials, and one of the second-generation drugs had pivotal trials that were randomized. All benefited from expedited approval. All HER2 monoclonal antibodies in the sample were based on randomized trials and expedited pathways., Conclusion: Second-generation TKI and monoclonal antibodies were often approved through expedited regulatory pathways and studied in single-arm trials. This helps to facilitate the approval for earlier use by patients, but is also associated with greater risk of post-approval safety-related labeling changes or unanticipated adverse events., (Copyright © 2019 Elsevier B.V. All rights reserved.)

This article compares gravimetry vs. high-performance liquid chromatography (HPLC) as quality control (QC) methods for paclitaxel, docetaxel and oxaliplatin preparations. We aimed at assessing the preparation method reliability in our hospital, evaluating compounding accuracy and estimating the influence of personnel training and standardized homogenization on compounding accuracy. Agreement, correlation, concordance, accuracy and precision between methods were evaluated for each drug. Conforming preparation percentages (CPs) at different tolerance limits (TLs) and compounding accuracy were calculated for each method and drug. Compounding accuracy was compared before and after personnel training and standardized homogenization implantation. SPSS v 20.0 and Ene v 2.0 were used. A total of 222 samples (58 docetaxel, 95 paclitaxel and 69 oxaliplatin) were analyzed. Gravimetry and HPLC are comparable methods. Overall CP was 81% for gravimetry at 10% TL and 85% for HPLC at 15% TL. Compounding accuracy is shown to be good for all methods and drugs. Homogenization optimization and personnel training make measurements more accurate for docetaxel and paclitaxel HPLC, but seem to worsen accuracy for docetaxel gravimetry. Gravimetry has shown to be a good alternative to HPLC for routine QC. Coupling with electronic methods should be considered in the future.

Background: Financial relationships between physicians and the pharmaceutical industry are common, but factors that may determine whether such relationships result in physician practice changes are unknown., Materials and Methods: We evaluated physician use of orally administered cancer drugs for four cancers: prostate (abiraterone, enzalutamide), renal cell (axitinib, everolimus, pazopanib, sorafenib, sunitinib), lung (afatinib, erlotinib), and chronic myeloid leukemia (CML; dasatinib, imatinib, nilotinib). Separate physician cohorts were defined for each cancer type by prescribing history. The primary exposure was the number of calendar years during 2013-2015 in which a physician received payments from the manufacturer of one of the studied drugs; the outcome was relative prescribing of that drug in 2015, compared with the other drugs for that cancer. We evaluated whether practice setting at a National Cancer Institute (NCI)-designated Comprehensive Cancer Center, receipt of payments for purposes other than education or research (compensation payments), maximum annual dollar value received, and institutional conflict-of-interest policies were associated with the strength of the payment-prescribing association. We used modified Poisson regression to control confounding by other physician characteristics., Results: Physicians who received payments for a drug in all 3 years had increased prescribing of that drug (compared with 0 years), for renal cell (relative risk [RR] 1.81, 95% confidence interval [CI] 1.58-2.07), CML (RR 1.22, 95% CI 1.08-1.39), and lung (RR 1.69, 95% CI 1.58-1.82), but not prostate (RR 0.97, 95% CI 0.93-1.02). Physicians who received compensation payments or >$100 annually had increased prescribing compared with those who did not, but NCI setting and institutional conflict-of-interest policies were not consistently associated with the direction of prescribing change., Conclusion: The association between industry payments and cancer drug prescribing was greatest among physicians who received payments consistently (within each calendar year). Receipt of payments for compensation purposes, such as for consulting or travel, and higher dollar value of payments were also associated with increased prescribing., Implications for Practice: Financial payments from pharmaceutical companies are common among oncologists. It is known from prior work that oncologists tend to prescribe more of the drugs made by companies that have given them money. By combining records of industry gifts with prescribing records, this study identifies the consistency of payments over time, the dollar value of payments, and payments for compensation as factors that may strengthen the association between receiving payments and increased prescribing of that company's drug., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2019.)

United States Pharmacopeia Chapter <800>, concerned with the handling of hazardous drugs in healthcare settings, requires that any entity handling such drugs maintain a hazardous drug list. While this list must include any drug found on the latest NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings, entities are expected to include other drugs and substances of concern. This article provides guidance on the creation and maintenance of such a list., (Copyright© by International Journal of Pharmaceutical Compounding, Inc.)

Breast cancer treatment for women aged 70 years and older can be complicated by existing comorbidities, a shorter lifespan, and a greater risk of side effects from treatments such as chemotherapy. Identifying and continually assessing appropriate breast cancer treatment strategies in older women is important. This article highlights an approach to surgical treatment that demonstrates that age may not be the most important factor in surgical treatment for early-stage breast cancer.

Objectives: To compare US Food and Drug Administration (FDA) and European Medicines Agency (EMA) labeling for evidence based on patient-reported outcomes (PROs) of new oncology treatments approved by both agencies., Methods: Oncology drugs and indications approved between 2012 and 2016 by both the FDA and the EMA were identified. PRO-related language and analysis reported in US product labels and drug approval packages and EMA summaries of product characteristics were compared for each indication., Results: In total, 49 oncology drugs were approved for a total of 64 indications. Of the 64 indications, 45 (70.3%) included PRO data in either regulatory submission. No FDA PRO labeling was identified. PRO language was included in the summary of product characteristics for 21 (46.7%) of 45 indications. European Organisation for Research and Treatment of Cancer and Functional Assessment of Cancer Therapy measures were used frequently in submissions. FDA's comments suggest that aspects of study design (eg, open labels) or the validity of PRO measures was the primary reason for the lack of labeling based on PRO endpoints. Both agencies identified missing PRO data as problematic for interpretation., Conclusions: During this time period, the FDA and the EMA used different evidentiary standards to assess PRO data from oncology studies, with the EMA more likely to accept data from open-label studies and broad concepts such as health-related quality of life. An understanding of the key differences between the agencies may guide sponsor PRO strategy when pursuing labeling. Patient-focused proximal concepts are more likely than distal concepts to receive positive reviews., (Copyright © 2019. Published by Elsevier Inc.)

Afatinib, trametinib and regorafenib are three costly oral oncology drugs with a short shelf-life after the original container has been opened. Their short shelf-lives are due to degradation on exposure to moisture. Therefore, manufacturers recommend them to be dispensed in the original packaging with the desiccant. However, the prescribed quantities do not always match the quantities in the original packaging, usually because of dose modifications for toxicities. This leads to potentially significant drug wastage and financial losses. We describe some potential approaches to this issue.

Aim: To establish a standard reference for bioactivity of widely used anticancer compounds that might be useful for meaningful interpretation of the cell viability data generated for novel synthetic derivatives., Materials & Methods: Meta-analysis of published IC50 values was carried out for commonly used anticancer compounds and cell viability experiments were performed to validate the role of certain factors in drug activity., Results & Conclusion: Variability in the published IC50 values was demonstrated. Based on median IC50 values derived from pooled published data, cell lines were classified as either sensitive or resistant. Further, factors that influence IC50 values were discussed, thus encouraging researchers to devise more rational experimental approaches to enhance the success rate in later stages of drug development.

Quinolizidine alkaloids, a main form of alkaloids found in the genus Sophora, have been shown to have many pharmacological effects. This review aims to summarize the photochemical reports and biological activities of quinolizidine alkaloids in Sophora. The collected information suggested that a total of 99 quinolizidine alkaloids were isolated and detected from different parts of Sophora plants, represented by lupinine-type, cytisine-type, sparteine-type, and matrine-type. However, quality control needs to be monitored because it could provide basic information for the reasonable and efficient use of quinolizidine alkaloids as medicines and raw materials. The nonmedicinal parts may be promising to be used as a source of quinolizidine alkaloid raw materials and to reduce the waste of resources and environmental pollution. In addition, the diversity of chemical compounds based on the alkaloid scaffold to make a biological compound library needs to be extended, which may reduce toxicity and find new bioactivities of quinolizidine alkaloids. The bioactivities most reported are in the fields of antitumor activity along with the effects on the cardiovascular system. However, those studies rely on theoretical research, and novel drugs based on quinolizidine alkaloids are expected., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Competing Interests: DisclosuresThe authors have declared no potential conflicts of interest.

Chemotherapy order review by pharmacists requires careful attention to many details, and serious consequences can occur if errors are made. Other high-risk industries have long used checklists to improve accuracy and reduce the risk of errors. Despite the recent expansion of checklist use in other areas of medicine, there is currently no published evidence that checklists are being widely used by pharmacists in the evaluation of chemotherapy orders. This article explains a flexible checklist called PRONTO (Patient, Regimen, Organ Function, Numbers, Toxicity, Order Verification) that has been successfully used by pharmacists in variety of practice settings in two academic centers in North Carolina. Proposed benefits of using a checklist in order review include standardization of review for better communication between collaborating pharmacists, a training tool for new or cross-training pharmacists, and an educational tool for students.

Objectives: To review the existing glioma literature and National Comprehensive Cancer Network current standard-of care guidelines for recurrent high-grade glioma, which includes surgery, radiation, and systemic therapies., Data Sources: PubMed, MedlinePlus, Science Direct, National Comprehensive Cancer Network, and Google Scholar were searched. Key words for databases were high-grade glioma, glioblastoma, recurrent, surgery, radiation, and systemic therapy., Conclusion: Approved treatments for patients with recurrent high-grade glioma are limited and do not significantly impact progression-free survival rates, nor do they offer long-term benefit in symptom improvement or quality of life. Particular consideration for progression versus pseudoprogression should be evaluated before pursuing recurrent therapies., Implications for Nursing Practice: Given the limited availability of standard-of-care treatments, clinical trials should be prioritized to maximize future treatment options. Individual performance status, genetic and molecular profiles, as well as goals of care and quality of life are important considerations in the context of treatment plans., (Copyright © 2018. Published by Elsevier Inc.)

Objective: To identify the practice differences among chemotherapy units and the opinions of pharmacists on safety precautions for handling antineoplastic drugs in hospitals., Method: The survey was administered to hospital pharmacists in Turkey. The pharmacists who work in chemotherapeutic drug preparation units were asked to participate if they are volunteered. The participating pharmacists were asked questions about the type of chemotherapy units, order and verification process of chemotherapy protocols and potential shortcomings of chemotherapy preparation. The questions were initially assessed in a small sample of pharmacists and subsequently revised and refined. The filled and returned questionnaires were accepted as given consent., Results: A total of 97 questionnaires were delivered and 40 (41%) were returned by pharmacists. The median age and practicing years in hospitals of the pharmacists were 38.0 and 6.25 years, respectively. Fully automated chemotherapy units were used by 42.5% of respondents, whereas 30% prepare chemotherapeutics manually; furthermore, 87.5% provide chemotherapeutic drug preparations (admixtures) less than 120 per day. With regard to the drug preparation process, more than half of the respondents 'always' use protective equipment without foot covers (32.3%). Almost 90% of respondents 'always' use a coat, mask and biological safety cabinets; however, 20% of respondents 'often' use closed-system drug transfer sets. More than 50% of pharmacists expressed that they have sufficient knowledge on cytotoxics and the risk of exposure, protective precautions, selection and usage of personal protective equipment and correct storage of cytotoxics., Conclusion: Pharmacists acknowledge sufficient understanding of safe preparation and handling of chemotherapeutics, but reported practices by pharmacists in hospitals are not consistent with published recommendations. Providing theoretical and practical educations for pharmacists and developing standard procedures for preparing chemotherapy may be beneficial in improving the preparation and use of antineoplastics in Turkey.

Background: Following approval of the Biologics Price Competition and Innovation Act of 2009, biosimilars are gradually entering the market in the United States. With the introduction of more biosimilars into the marketplace, all healthcare providers should be familiar with the approval and evaluation process, the naming convention applied to these agents, and the importance of accurate pharmacovigilance., Objectives: This article aims to describe the approval process of biosimilars, including extrapolation, and to help healthcare providers understand when a biosimilar may be interchanged for the reference biologic and the naming convention used for biosimilars. In addition, this article explores how these topics affect confidence in dispensing and pharmacovigilance., Methods: A literature review was conducted, and search terms and variation included biosimilar agents AND FDA approval, legislation, interchangeability, naming conventions, confidence in dispensing, and pharmacovigilance., Findings: Healthcare providers involved in the dispensing and administration of biosimilar and interchangeable biologics need to be continually educated to ensure confidence, familiarity, and accuracy with the processes surrounding biosimilars.

Background: With the advent of biosimilars into the U.S. healthcare market, knowledge deficits exist for nurses and patients regarding the regulatory approval process and key nursing considerations for each of these new medications., Objectives: This article provides essential clinical information for oncology nurses who are directly involved in patient care who will be administering U.S. Food and Drug Administration (FDA)-approved biosimilars for oncologic use. Oncology nurses must be informed on their therapeutic uses, mechanisms of action, and administration considerations., Methods: An overview of biosimilars in the United States is given, and each FDA-approved oncology biosimilar medication is described in detail., Findings: Oncology biosimilars are safe and effective treatment options that may increase patient access, decrease healthcare costs through competition, and improve the lives of patients with certain malignancies. Nurses are in key roles in patient care to foster the transition from previously patented, branded, and expensive medications to biosimilars that can achieve the same desired effects for a lower cost.