Comparison of permitted daily exposure (PDE) values for active pharmaceutical ingredients (APIs) - Evidence of a robust approach.

Permitted Daily Exposure Limits (PDEs) are set for Active Pharmaceutical Ingredients (APIs) to control cross-contamination when manufacturing medicinal products in shared facilities. With the lack of official PDE lists for pharmaceuticals, PDEs have to be set by each company separately. Although general rules and guidelines for the setting of PDEs exist, inter-company variations in the setting of PDEs occur and are considered acceptable within a certain range. To evaluate the robustness of the PDE approach between different pharmaceutical companies, data on PDE setting of five marketed APIs (amlodipine, hydrochlorothiazide, metformin, morphine, and omeprazole) were collected and compared. Findings show that the variability between PDE values is within acceptable ranges (below 10-fold) for all compounds, with the highest difference for morphine due to different Point of Departures (PODs) and Adjustment Factors (AFs). Factors of PDE variability identified and further discussed are: (1) availability of data, (2) selection of POD, (3) assignment of AFs, (4) route-to-route extrapolation, and (5) expert judgement and differences in company policies. We conclude that the investigated PDE methods and calculations are robust and scientifically defensible. Additionally, we provide further recommendations to harmonize PDE calculation approaches across the pharmaceutical industry.

Care Fragmentation and Mortality in Readmission after Surgery for Hepatopancreatobiliary and Gastric Cancer: A Patient-Level and Hospital-Level Analysis of the Healthcare Cost and Utilization Project Administrative Database.

BACKGROUND: Hepatopancreatobiliary (HPB) and gastric oncologic operations are frequently performed at referral centers. Postoperatively, many patients experience care fragmentation, including readmission to "outside hospitals" (OSH), which is associated with increased mortality. Little is known about patient-level and hospital-level variables associated with this mortality difference. STUDY DESIGN: Patients undergoing HPB or gastric oncologic surgery were identified from select states within the Healthcare Cost and Utilization Project database (2006-2014). Follow-up was 90 days after discharge. Analyses used Kruskal-Wallis test, Youden index, and multilevel modeling at the hospital level. RESULTS: There were 7,536 patients readmitted within 90 days of HPB or gastric oncologic surgery to 636 hospitals; 28% of readmissions (n = 2,123) were to an OSH, where 90-day readmission mortality was significantly higher: 8.0% vs 5.4% (p < 0.01). Patients readmitted to an OSH lived farther from the index surgical hospital (median 24 miles vs 10 miles; p < 0.01) and were readmitted later (median 25 days after discharge vs 12; p < 0.01). These variables were not associated with readmission mortality. Surgical complications managed at an OSH were associated with greater readmission mortality: 8.4% vs 5.7% (p < 0.01). Hospitals with <100 annual HPB and gastric operations for benign or malignant indications had higher readmission mortality (6.4% vs 4.7%, p = 0.01), although this was not significant after risk-adjustment (p = 0.226). CONCLUSIONS: For readmissions after HPB and gastric oncologic surgery, travel distance and timing are major determinants of care fragmentation. However, these variables are not associated with mortality, nor is annual hospital surgical volume after risk-adjustment. This information could be used to determine safe sites of care for readmissions after HPB and gastric surgery. Further analysis is needed to explore the relationship between complications, the site of care, and readmission mortality.

Inability to manage non-severe complications on an outpatient basis increases non-white patient readmission rates after pancreaticoduodenectomy: A large metropolitan tertiary care center experience.

BACKGROUND: Pancreaticoduodenectomy (PD) has a high rate of readmission, and racial disparities in care could be an important contributor. METHODS: Patients undergoing PD were prospectively followed, and their complications graded using the Modified Accordion Grading System (MAGS). Patient factors and perioperative outcomes for patients with and without postoperative readmission were compared in univariate and multivariate analysis by severity. RESULTS: 837 patients underwent PD, the overall 90-day readmission rate was 27.5%. Non-white race was independently associated with readmission (OR 1.83, p = 0.007). 51.3% of readmissions were for non-severe complications (MAGS <3). Non-white race was independently associated with MAGS non-severe readmission (OR 2.13, p = 0.006), but not MAGS severe readmission. CONCLUSIONS: Non-white patients are more likely to be readmitted, particularly for non-severe complications. Follow up protocols should be tailored to address race disparities in the rates of readmission as readmission for less severe complications could potentially be avoidable.

A cross-industry collaboration to assess if acute oral toxicity (Q)SAR models are fit-for-purpose for GHS classification and labelling.

This study assesses whether currently available acute oral toxicity (AOT) in silico models, provided by the widely employed Leadscope software, are fit-for-purpose for categorization and labelling of chemicals. As part of this study, a large data set of proprietary and marketed compounds from multiple companies (pharmaceutical, plant protection products, and other chemical industries) was assembled to assess the models' performance. The absolute percentage of correct or more conservative predictions, based on a comparison of experimental and predicted GHS categories, was approximately 95%, after excluding a small percentage of inconclusive (indeterminate or out of domain) predictions. Since the frequency distribution across the experimental categories is skewed towards low toxicity chemicals, a balanced assessment was also performed. Across all compounds which could be assigned to a well-defined experimental category, the average percentage of correct or more conservative predictions was around 80%. These results indicate the potential for reliable and broad application of these models across different industrial sectors. This manuscript describes the evaluation of these models, highlights the importance of an expert review, and provides guidance on the use of AOT models to fulfill testing requirements, GHS classification/labelling, and transportation needs.

Deriving harmonised permitted daily exposures (PDEs) for paracetamol (acetaminophen) CAS #: 103-90-2.

In the pharmaceutical industry, cleaning criteria are required for multipurpose manufacturing facilities. These Health Based Exposure Limits (HBELs), also called permitted daily exposures (PDEs) values, are derived from toxicological and pharmacological evaluation of the active pharmaceutical ingredients (APIs). The purpose of this publication is to show an example of how authors from different companies evaluate a generic drug, paracetamol, and discuss different approaches and relevance of the nonclinical studies for deriving PDEs. PDE limits of 25 mg/day for the oral route, and 20 mg/day for the intravenous (i.v.) and inhalation (inhal.) routes, respectively, were established herein. However, it has been already recognised that there are acceptable differences in the PDE calculations, which may be based on data accessibility, company-specific science-policy decisions or expert judgments. These differences can cause up to a 3-fold lower or higher values. If unnecessarily high factors are applied, this would result in a very conservative PDE value and unneeded additional cleaning and higher manufacturing costs. The PDE values presented are considered to be protective against adverse and pharmacological effects observed in clinical trials and in this case, a very long postmarketing period of paracetamol.

Assessment of Hepatic Arterial Infusion of Floxuridine in Combination With Systemic Gemcitabine and Oxaliplatin in Patients With Unresectable Intrahepatic Cholangiocarcinoma: A Phase 2 Clinical Trial.

IMPORTANCE: Unresectable intrahepatic cholangiocarcinoma (IHC) carries a poor prognosis, with a median overall survival (OS) of 11 months. Hepatic arterial infusion (HAI) of high-dose chemotherapy may have potential benefit in these patients. OBJECTIVE: To evaluate clinical outcomes when HAI chemotherapy is combined with systemic chemotherapy in patients with unresectable IHC. DESIGN, SETTING, AND PARTICIPANTS: A single-institution, phase 2 clinical trial including 38 patients was conducted with HAI floxuridine plus systemic gemcitabine and oxaliplatin in patients with unresectable IHC at Memorial Sloan Kettering Cancer Center between May 20, 2013, and June 27, 2019. A confirmatory phase 1/2 study using the same therapy was conducted during the same time period at Washington University in St Louis. Patients with histologically confirmed, unresectable IHC were eligible. Resectable metastatic disease to regional lymph nodes and prior systemic therapy were permitted. Patients with distant metastatic disease were excluded. INTERVENTIONS: Hepatic arterial infusion of floxuridine and systemic administration of gemcitabine and oxaliplatin. MAIN OUTCOMES AND MEASURES: The primary outcome was progression-free survival (PFS) of 80% at 6 months. RESULTS: For the phase 2 clinical trial at Memorial Sloan Kettering Cancer Center, 42 patients with unresectable IHC were included and, of these, 38 patients were treated (13 [34%] men; median [range] age at diagnosis, 64 [39-81] years). The median follow-up was 30.5 months. Twenty-two patients (58%) achieved a partial radiographic response, and 32 patients (84%) achieved disease control at 6 months. Four patients had sufficient response to undergo resection, and 1 patient had a complete pathologic response. The median PFS was 11.8 months (1-sided 90% CI, 11.1) with a 6-month PFS rate of 84.1% (90% CI, 74.8%-infinity), thereby meeting the primary end point (6-month PFS rate, 80%). The median OS was 25.0 months (95% CI, 20.6-not reached), and the 1-year OS rate was 89.5% (95% CI, 80.2%-99.8%). Patients with resectable regional lymph nodes (18 [47%]) showed no difference in OS compared with patients with node-negative disease (24-month OS: lymph node negative: 60%; 95% CI, 40%-91% vs lymph node positive: 50%; 95% CI, 30%-83%; P = .66). Four patients (11%) had grade 4 toxic effects requiring removal from the study (1 portal hypertension, 2 gastroduodenal artery aneurysms, 1 infection in the pump pocket). Subgroup analysis showed significant improvement in survival in patients with IDH1/2 mutated tumors (2-year OS, 90%; 95% CI, 73%-99%) vs wild-type (2-year OS, 33%; 95% CI, 18%-63%) (P = .01). In the Washington University in St Louis confirmatory cohort, 9 patients (90%) achieved disease control at 6 months; the most common grade 3 toxic effect was elevated results of liver function tests, and median PFS was 12.8 months (1-sided 90% CI, 6.4). CONCLUSIONS AND RELEVANCE: Hepatic arterial infusion plus systemic chemotherapy appears to be highly active and tolerable in patients with unresectable IHC; further evaluation is warranted.

Surgeon Variation in Intraoperative Supply Cost for Pancreaticoduodenectomy: Is Intraoperative Supply Cost Associated with Outcomes?

BACKGROUND: With increased scrutiny on the quality and cost of health care, surgeons must be mindful of their outcomes and resource use. We evaluated surgeon-specific intraoperative supply cost (ISC) for pancreaticoduodenectomy and examined whether ISC was associated with patient outcomes. STUDY DESIGN: Patients undergoing open pancreaticoduodenectomy between January 2012 and March 2015 were included. Outcomes were tracked prospectively through postoperative day 90, and ISC was defined as the facility cost of single-use surgical items and instruments, plus facility charges for multiuse equipment. Multivariate logistic regression was used to test associations between ISC and patient outcomes using repeated measures at the surgeon level. RESULTS: There were 249 patients who met inclusion criteria. Median ISC was $1,882 (interquartile range [IQR] $1,497 to $2,281). Case volume for 6 surgeons ranged from 18 to 66. Median surgeon-specific ISC ranged from $1,496 to $2,371. Greater case volume was associated with decreased ISC (p < 0.001). Overall, ISC was not predictive of postoperative complications (p = 0.702) or total hospitalization expenditures (p = 0.195). At the surgeon level, surgeon-specific ISC was not associated with the surgeon-specific incidence of severe complication or any wound infection (p > 0.227 for both), but was associated with delayed gastric emptying (p = 0.004) and postoperative pancreatic fistula (p < 0.001). CONCLUSIONS: In a single-institution cohort of 249 pancreaticoduodenectomies, high-volume surgeons tended to be low-cost surgeons. Across the cohort, ISC was not associated with outcomes. At the surgeon level, associations were noted between ISC and complications, but these may be attributable to unmeasured differences in the postoperative management of patients. These findings suggest that quality improvement efforts to restructure resource use toward more cost-effective practice may not affect patient outcomes, although prospective monitoring of safety and effectiveness must be of the utmost concern.

Utility of a multidisciplinary tumor board in the management of pancreatic and upper gastrointestinal diseases: an observational study.

BACKGROUND & OBJECTIVES: Multidisciplinary tumor boards (MDTBs) are frequently employed in cancer centers but their value has been debated. We reviewed the decision-making process and resource utilization of our MDTB to assess its utility in the management of pancreatic and upper gastrointestinal tract conditions. METHODS: A prospectively-collected database was reviewed over a 12-month period. The primary outcome was change in management plan as a result of case discussion. Secondary outcomes included resources required to hold MDTB, survival, and adherence to treatment guidelines. RESULTS: Four hundred seventy cases were reviewed. MDTB resulted in a change in the proposed plan of management in 101 of 402 evaluable cases (25.1%). New plans favored obtaining additional diagnostic workup. No recorded variables were associated with a change in plan. For newly-diagnosed cases of pancreatic ductal adenocarcinoma (n = 33), survival time was not impacted by MDTB (p = .154) and adherence to National Comprehensive Cancer Network guidelines was 100%. The estimated cost of physician time per case reviewed was $190. CONCLUSIONS: Our MDTB influences treatment decisions in a sizeable number of cases with excellent adherence to national guidelines. However, this requires significant time expenditure and may not impact outcomes. Regular assessments of the effectiveness of MDTBs should be undertaken.

Cost variation in a laparoscopic cholecystectomy and the association with outcomes across a single health system: implications for standardization and improved resource utilization.

BACKGROUND: Payers and regulatory bodies are increasingly placing emphasis on cost containment, quality/outcome measurement and transparent reporting. Significant cost variation occurs in many operative procedures without a clear relationship with outcomes. Clear cost-benefit associations will be necessary to justify expenditures in the era of bundled payment structures. METHODS: All laparoscopic cholecystectomies (LCCKs) performed within a single health system over a 1-year period were analysed for operating room (OR) supply cost. The cost was correlated with American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) outcomes. RESULTS: From July 2013 to June 2014, 2178 LCCKs were performed by 55 surgeons at seven hospitals. The median case OR supply cost was $513 ± 156. There was variation in cost between individual surgeons and within an individual surgeon's practice. There was no correlation between cost and ACS NSQIP outcomes. The majority of cost variation was explained by selection of trocar and clip applier constructs. CONCLUSIONS: Significant case OR cost variation is present in LCCK across a single health system, and there is no clear association between increased cost and NSQIP outcomes. Placed within the larger context of overall cost, the opportunity exists for improved resource utilization with no obvious risk for a reduction in the quality of care.

The impact of recent hospitalization on surgical site infection after a pancreatectomy.

BACKGROUND: Surgical site infections (SSI) are a major cause of increased morbidity and cost after a pancreatectomy. Patients undergoing a pancreatectomy frequently have had recent inpatient hospital admissions prior to their surgical admission (recent pre-surgical admission, RPSA), which could increase the risk of SSI. METHODS: The 2009-2011 Healthcare Cost Utilization Project California State Inpatient Database was used. Chi-square tests, Student's t-tests and multivariable logistic regression were used. RESULTS: Three thousand three hundred and seventy-six patients underwent a pancreatectomy, and 444 (13.2%) had RPSA. One hundred and eighty (40.5%) RPSAs were to different hospitals other than where patients' pancreatectomy took place. In univariate analysis, patients with RPSA had a significantly higher rate of post-operative SSIs, and this was associated with a longer length of post-operative stay, higher post-operative hospital costs and increased postoperative 30-day readmission rates (Table 1). In Multivariate analysis, RPSA was an independent predictor of post-operative SSI [odds ratio (OR) = 1.68, P = 0.013], and the risk of SSI increased with increasing RPSA length of stay (OR = 1.07 per day, P = 0.001). CONCLUSIONS: Recent pre-surgical admission is an important risk factor for SSI after a pancreatectomy. Many patients with RPSA are not admitted pre-operatively to the same hospital where the pancreatectomy occurs; in such circumstances, SSI rates may not be a sole reflection of the care provided by operating hospitals.

Improved peri-operative outcomes with epidural analgesia in patients undergoing a pancreatectomy: a nationwide analysis.

BACKGROUND: In spite of limited evidence demonstrating a benefit, epidural analgesia (EA) is often used for patients undergoing a pancreatectomy. In the present study, the impact of epidural analgesia on post-operative outcomes after a pancreatectomy is examined. METHODS: Utilizing the Nationwide Inpatient Sample, the effect of EA on peri-operative outcomes after a pancreatectomy was examined. Multivariable logistic and linear regression with propensity score matching were utilized for risk adjustment. RESULTS: From 2008-2011, 12,440 patients underwent a pancreatectomy. Of these, 1130 (9.1%) patients received epidural analgesia. Using univariate comparison, patients receiving EA had a significantly decreased length of stay (LOS), hospital charges and post-operative inpatient mortality. In multivariate analyses, EA was independently associated with a decreased post-operative LOS (adjusted mean difference = -1.19 days, P < 0.001), decreased hospital charges (adjusted mean difference = -$16,814, P = 0.002) and decreased post-operative inpatient mortality [adjusted odds ratio (OR) = 0.42, P < 0.001]. Using 1:1 propensity score matching, patients who received an EA (n = 1070) had significantly decreased post-operative LOS (11.0 versus 12.1 days, P = 0.011), lower hospital charges ($112,086 versus $128,939, P = 0.001) and decreased post-operative inpatient mortality (1.5% versus 3.6%, P = 0.002) compared with matched controls without EA (n = 1070). CONCLUSION: Analysis of a large hospital database reveals that EA is associated with improved peri-operative outcomes after a pancreatectomy. Additional studies are required to understand fully if this relationship is causal.

Cost benefit analysis of mesh reinforcement of stapled left pancreatectomy.

OBJECTIVES: Pancreatic leak is a morbid complication following left pancreatectomy, which results in prolonged hospitalization, additional diagnostic testing and invasive procedures. The present authors have previously demonstrated that mesh reinforcement of stapled left pancreatectomy results in fewer pancreatic leaks. This study was conducted to investigate whether mesh reinforcement also results in cost benefits for the health care system. METHODS: A cost benefit model was developed to estimate net cost savings from the payer's perspective. The model is based on the results of a randomized, single-blinded trial of mesh versus no mesh reinforcement of the pancreatic remnant after left pancreatectomy. A two-way sensitivity analysis was conducted to determine the model's sensitivity to fluctuations in the cost of mesh and the effectiveness of the mesh in reducing clinically significant leaks. RESULTS: Average total costs for an episode of care were US$13 337 and US$15 505 for patients who did and did not receive mesh, respectively, which indicates savings of US$2168. Two-way sensitivity analysis showed that, given a probability of 1.9% for developing a clinically significant leak in patients in whom mesh reinforcement was used, the strategy would continue to save costs if mesh were priced at ≤US$1804. CONCLUSIONS: Mesh reinforcement decreases clinically significant pancreatic leaks. Despite the additional cost of mesh reinforcement, the use of mesh reinforcement results in overall cost savings for the health care system because of the resultant decrease in the occurrence of clinically significant leaks.

Reduction of surgical site infection using a novel intervention (ROSSINI): study protocol for a randomised controlled trial.

BACKGROUND: Surgical site infection (SSI) is a common complication following abdominal surgery. It is associated with considerable morbidity and mortality, and its management results in significant cost to health services within both primary and secondary care. Some surgeons believe that the use of a wound-edge protection device may reduce the incidence of SSI. Whilst there is some encouraging evidence showing that such devices may lead to a reduction in SSI, there are no controlled trials of sufficient size or quality to support their routine use. METHODS/DESIGN: 750 patients will be recruited from around 20 surgical units within the United Kingdom. Patients undergoing laparotomy through any major abdominal incision for any indication, elective or emergency, are eligible. Patients under the age of 18, those undergoing a laparoscopic assisted procedure or who have undergone laparotomy within the previous 3 months, and those who are unable to give informed consent will be excluded. Patients will be randomised (1:1 ratio) to the use of a wound-edge protection device or no wound-edge protection device during surgery. Follow up will consist of blinded clinical wound reviews at 5-7 days and 30-33 days postoperatively with a self-completed questionnaire covering the intervening period. Quality of life questionnaires will be completed prior to surgery and at the subsequent wound review points and information on resource usage will also be captured.The primary outcome measure is SSI within 30 days of surgery. Secondary outcomes include the impact of the degree of wound contamination, patient comorbidity, and operative characteristics on the efficacy of a wound-edge protection device in reducing SSI and whether the use of a wound-edge protection device has an effect on health-related quality of life or length of hospital stay and is cost-effective. DISCUSSION: Rossini is the first multicentre observer-blinded randomised controlled trial of sufficient size and quality to establish whether the use of a wound-edge protection device in adult patients undergoing abdominal surgery leads to a lower rate of SSI. The results of this study will be used to inform current surgical practice and may potentially benefit patients undergoing surgery in the future. TRIAL REGISTRATION NUMBER: Current Controlled Trials ISRCTN: ISRCTN40402832.

Ethical management of conflict of interest: proposed standards for academic surgical societies.

BACKGROUND: A significant increase in industry support of professional medical associations coupled with data suggesting that gifts from industry have significant clinical influence have prompted calls from the Institute of Medicine and physician leaders to identify and manage conflicts of interest that stem from financial support of professional medical associations by industry. STUDY DESIGN: A joint task force of members appointed by the Association for Academic Surgery and the Society of University Surgeons was convened in July 2009. Recommendations were developed regarding management of all potential conflicts of interest that can arise within the context of an academic surgical society, with specific focus on relationships with industry. Task force members reached consensus around each recommendation and the guidelines were subsequently adopted by the Executive Councils of both societies. RESULTS: The committee identified 4 primary areas of need for transparent and definitive management of conflict of interest: 1) individual society activities, including general budget support, society endorsements, and journal affiliation; 2) individual personnel conflicts such as society leadership and standards for disclosure of conflict; 3) meeting activities including budgetary support, program committee associations, and abstract review process; and 4) foundation support and research and travel awards. The resulting guidelines aim to protect the societies and their membership from undue bias that may undermine the credibility and mission of these associations. CONCLUSIONS: Policy guidelines to mitigate conflict of interest are necessary to protect the integrity of the work of academic surgical societies and their fiduciary duty to members and patients. Guidelines created and adopted by the Association for Academic Surgery and Society of University Surgeons form an effective model for academic surgical societies and their members.