CEO Roundtable Research Articles

Right-censoring bias in trials shared at the Project Data Sphere platform.

e13543 Background: Independent of the bias inherent to the design and execution of clinical trials, bias may be the result of patient censoring. A bias index (BI) was developed to detect right-censoring bias and tested in datasets availabe at Project Data Sphere, a data sharing research platform maintained by the CEO Roundtable on Cancer, Inc.,* a nonprofit corporation to improve outcomes for cancer patients by openly sharing deidentified data. Methods: Project Data Sphere platform was searched for clinical comparative trials with available experimental and comparator survival datasets: overall survival (OS) and event-free survival (EFS: disease-free survival, DFS, or progresssion-free survival, PFS). The R language and the integrated development environment Rstudio were used to import and manage the datasets. BI was defined in the events time domain as the adjusted proportion of censor times below the mean event time. Comparison of BI in different datasets were made with the two-sided Wilcoson unpaired test. A weighted regression model was applied to estimate the influence of bias on survival results as measured by the hazard ratio (HR). Results: Out of 184 trials, 19 trials offered both comparator and experimental arms, 3 of them not based on survival analysis and 4 of them with 2 substudies, providing 72 datasets based on OS and/or EFS, for a total of 16532 patients (90.8% of the 18198 patients in published trials). BI over the theshold was found in 24% of EFS datasets (versus 0% in OS datasets, Wilcoxon p = 0.0007), especially in PFS (35% vs 0% in DFS datasets, p = 0.00004). Nearly two thirds of the variance in the HR of EFS datasets was explained by the HR of OS datasets (adj.R2 = 0.638, p = 1.5e-5), approaching to what was found in the corresponding publications (adj.R2 = 0.751, p = 7.81e-5). Though the trials sample is small, introducing the BI of control and experimental datasets in the model decreases the residual standard error (3.831 vs 3.958) and increases the correlation (adj.R2 = 0.99, p < 2.2e-16), resulting in the model: HR(EFR) = 0.985 HR(OS) + 0.36 BI(exper) – 0.42 BI(control). Conclusions: This study is a proof of concept that right-censoring bias may be detected and estimated in clinical trials, especially in PFS datasets, and opens the possibility for correcting biased estimations in survival and increasing the precision in the prediction of OS from preliminary EFS. (*) This abstract is based on research using information obtained from ProjectDataSphere.org, which is maintained by Project Data Sphere LLC. Neither Project Data Sphere nor the owners of any information from the web site have contributed to, approved or are in any way responsible for the contents of this abstract.

Antibacterial Use Is Associated with an Increased Risk of Hematologic and Gastrointestinal Adverse Events in Patients Treated with Gemcitabine for Stage IV Pancreatic Cancer.

Preclinical evidence has demonstrated that common intratumor bacteria metabolize the chemotherapeutic drug gemcitabine. The significance of this bacterial metabolism pathway, relative to the known metabolic pathways by host enzymes, is not known. We hypothesized that bacterial metabolism is clinically significant and that "knockdown" by antibacterial therapy has the unintended effect of increasing the effective dose of gemcitabine, thereby increasing the risk for gemcitabine-associated toxicities. We reanalyzed the comparator arm of the MPACT trial (NCT01442974), made available through Project Data Sphere, LLC (CEO Roundtable on Cancer's Life Sciences Consortium, Cary, NC; www.projectdatasphere.org). In this arm, 430 patients with metastatic pancreatic adenocarcinoma were treated with gemcitabine. We used the Anderson-Gill survival model to compare the risk of developing an adverse event after antibacterial prescription with time unexposed to antibacterials. Adverse events of grade 3 and greater were considered at three levels of granularity: all aggregated into one endpoint, aggregated by class, and taken individually. Antibiotic exposures were analyzed in aggregate as well as by class. Antibacterial exposure was associated with an increased risk of adverse events (hazard ratio [HR]: 1.77; confidence interval [CI]: 1.46-2.14), any hematologic adverse event (HR: 1.64; CI: 1.26-2.13), and any gastrointestinal adverse event (HR: 2.14; CI: 1.12-4.10) but not a constitutional (HR: 1.33; CI: 0.611-2.90) or hepatologic adverse event (HR: 0.99; CI: 0.363-2.71). Among specific adverse events, antibacterial exposure was associated with an increased risk of anemia (HR: 3.16; CI: 1.59-6.27), thrombocytopenia (HR: 2.52; CI: 1.31-4.85), leukopenia (HR: 3.91; CI: 1.46-10.5), and neutropenia (HR: 1.53; CI: 1.07-2.17) but not any other specific adverse events. Antibacterial exposure was associated with an increased risk of gemcitabine-associated, dose-limiting adverse events, including aggregate hematologic and gastrointestinal events, as well as four specific hematologic adverse events, suggesting that intratumor bacteria may be responsible for a clinically significant portion of gemcitabine metabolism. Alternative avenues of evidence will be necessary to confirm this preliminary finding and assess its generalizability. There is plentiful opportunity for similar analyses on other clinical trial data sets, where gemcitabine or other biomimetic small molecules were used. Patients treated with gemcitabine for metastatic pancreatic ductal adenocarcinoma have an increased rate of gemcitabine-associated toxicity during and after antibiotic therapy. This observation is consistent with preclinical evidence that intratumor bacteria metabolize gemcitabine to an inactive form. Further research is needed to determine whether this observation merits any changes in clinical practice.

Serum-based biomarkers and liver metastases in metastatic castration-resistant prostate cancer (mCRPC).

372 Background: Metastatic castrate-resistant prostate cancer patients with liver metastases have a poor prognosis. No large studies to date have investigated the clinical and biochemical parameters associated with liver metastases in this population. Methods: Patient data was obtained from 1,281 men with mCRPC that were enrolled on to three phase III clinical trials for the treatment of their disease. This clinical trial data was obtained from Project Data Sphere (www.projectdatasphere.org), an initiative of the CEO Roundtable on Cancer's Life Sciences Consortium. Multiple logistic regression was performed on clinical and biochemical baseline variables to test their association with the presence of liver metastases on baseline CT/MRI imaging. Variables assessed included prior docetaxel exposure, ECOG performance status, albumin, alkaline phosphatase (ALP), alanine transaminase (ALT), aspartate transaminase (AST), hemoglobin, lactate dehydrogenase (LDH), prostate specific antigen (PSA), and total bilirubin. The investigation included lab variables when treated as both dichotomous (based on normal-abnormal ranges) and continuous. Results: Multiple variable analysis demonstrated that an abnormally elevated serum AST and/or LDH was associated with an increased likelihood of having documented radiographic liver metastases (p < 0.0001). The predicted probability of having liver metastases for an abnormally elevated AST or LDH was 13.90% (95% CI 9.12 – 20.59) and 16.80% (95% CI 13.19 – 21.16), respectively. Patients with both an elevated AST and LDH had a 31.31% (95% CI 24.0 – 39.73) probability of having liver metastases as compared to only 6.67% (95% CI 5.17 – 8.57) for those with normal values. The ROC curve for the final model (AST + LDH) containing dichotomous predictors was 0.6683 (p < 0.0001), which was not significantly different when treating the predictors as continuous (p = 0.4858). Conclusions: Our analysis demonstrated a significant association between the presence of liver metastases and elevated serum levels of AST and LDH. More research is needed to validate these biomarkers and determine their application in the clinical setting.

Overcoming barriers to develop a broad access data sharing platform.

e17690 Background: Analysis of Phase 3 clinical trial data is uncommon beyond the pre-defined protocol. Project Data Sphere, LLC (PDS), an independent initiative of the non-profit CEO Roundtable on...

The project data sphere initiative: accelerating cancer research by sharing data.

Background. Inthispaper,weprovidebackgroundandcontext regarding the potential for a new data-sharing platform, the ProjectDataSphere(PDS)initiative,fundedbyfinancialandinkind contributions from the CEO Roundtable on Cancer, to transform cancer research and improve patient outcomes. Giventherelativelymodestdeclineincancerdeath ratesover the past several years, a new research paradigm is needed to accelerate therapeutic approaches for oncologic diseases. Phase III clinical trials generate large volumes of potentially usable information, often on hundreds of patients, including patientstreatedwithstandardofcaretherapies(i.e.,controls). Both nationally and internationally, a variety of stakeholders have pursued data-sharing efforts to make individual patientlevel clinical trial data available to the scientific research community.

Employers' Role in Cancer Prevention and Treatment—Developing Success Metrics for Use by the CEO Roundtable on Cancer

As evidence accumulates on the risk factors for cancer, it is becoming clearer that employers can play a significant role in the fight against the disease by creating a workplace conducive to lowering health risks. The CEO Roundtable on Cancer's CEO Cancer Gold Standard Program defines what companies can do to prevent cancer, detect it early, and ensure access to the best available treatments for those who are afflicted with the disease. This article describes how Johnson & Johnson incorporated the Cancer Gold Standard Program into its existing health promotion initiatives. Then, a framework is proposed that employers can use to monitor progress in cancer prevention and treatment enhancement efforts. Finally, health care eligibility, claims, and health risk assessment data are analyzed to quantify Johnson & Johnson's progress since implementation of the Cancer Gold Standard Program. Companies interested in initiating or furthering their health promotion efforts should consider joining groups such as the CEO Cancer Gold Standard. Collectively, companies have the ability to influence policy makers, payers, and the industry at large in changing behaviors and creating a culture of health and wellness in the fight against cancer.

Data Sphere Shares Clinical Trial Information

The CEO Roundtable on Cancer's Project Data Sphere aims to accelerate cancer research by establishing a neutral platform for publicly sharing clinical trial data from industry and academia.

Table of Contents

Abstract Ethical conundrum: Execs serve on each other's boards From The Board Doctor Ease board into budget season Fair warning: IRS will come down hard on excess benefit transactions Consider a CEO's roundtable for your community Include these resources in your orientation packet Resource Guide to Interacting with Board Members Try this with the board member who won't fundraise Policy: Board Member Authority Create major donors through board‐hosted house parties Tips From The Trenches Visit Board & Administrator on Facebook Help your board feel great about the person they hired Ten tested ideas for board member recognition Engage board members with these tips Plan your role in the audit

Diagnostic Errors—The Next Frontier for Patient Safety

1. Vevers V. Obama says WH will remain smoke-free. http://www.cbsnews.com /blogs/2008/12/08/politics/politicalhotsheet/entry4654231.shtml. Accessed December 9, 2008. 2. Reinberg S. Cancer to surpass heart disease as world’s leading killer. washingtonpost .com Web page. December 9, 2008. http://www.washingtonpost.com /wp-dyn/content/article/2008/12/09/AR2008120901814.html. Accessed December 10, 2008. 3. Centers for Disease Control and Prevention. Cigarette smoking among adults—United States, 2007 [published correction appears in MMWR Morb Mortal Wkly Rep. 2008;57(47):1281]. MMWR Morb Mortal Wkly Rep. 2008; 57(45):1221-1226. 4. Centers for Disease Control and Prevention. Smoking-attributable mortality, years of potential life lost, and productivity losses—United States, 2000-2004. MMWR Morb Mortal Wkly Rep. 2008;57(45):1226-1228. 5. American Nonsmokers’ Rights Foundation. Summary of 100% smokefree state laws and population protected by 100% US smokefree laws. January 4, 2009. http: //www.no-smoke.org/pdf/SummaryUSPopList.pdf. Accessed December 12, 2009. 6. Risbeck CA. ADHA smoking cessation initiative liaisons, II: partnering with tobacco quitlines. November 2007. http://findarticles.com/p/articles/mi_m1ANQ /is_/ai_n25015057. Accessed December 9, 2008. 7. WHO Framework Convention on Tobacco Control: third session of the conference of the parties to the WHO FCTC. http://www.who.int/fctc/en/. Accessed January 10, 2009. 8. Fiore M, Croyle RT, Curry SJ, et al. Preventing 3 million premature deaths and helping 5 million smokers quit: a national action plan for tobacco cessation. Am J Public Health. 2004;94(2):205-210. 9. Peto R, Lopez A. The future worldwide health effects of current smoking patterns. In: Boyle P, Gray N, Henningfield J, Seffrin J, Zatonski W, eds. Tobacco and Public Health: Science and Policy. New York, NY: Oxford University Press; 2004: 281-286. 10. Mackay J, Erikson M, Shafey O. The Tobacco Atlas. 2nd ed. Atlanta, GA: American Cancer Society; 2006. 11. Fiore MC, Jaen CR, Baker TB, et al. Treating tobacco use and dependence: 2008 update. Rockville, MD: US Dept of Health and Human Services; May 2008. http://www.surgeongeneral.gov/tobacco/. Accessed February 5, 2009. 12. National Institute of Allergy and Infectious Dieseases. Treatment of HIV infection. http://www.niaid.nih.gov/factsheets/treat-hiv.htm. Updated November 8, 2007. Accessed February 8, 2009. 13. CEO Roundtable on Cancer Web page. http://www.ceoroundtableoncancer .org. Accessed December 19, 2008.

CEO Roundtable Allows VNAs to Share Successes

Carolyn Markey is the President and CEO of Visiting Nurse Associations of America. Direct correspondence to Jon Spampinato, Director of Communications, at [email protected] Printed with permission from VNAA.

Competitive intelligence at motorola

AbstractIn the fall issue (vol. 7, no. 3), we presented a symposium drawn from the panel discussions at the SCIP/Rutgers University CEO Roundtable on Competitive Intelligence, held last year in New York City. During that historic gathering, some of the CEO participants advocated in favor of establishing dedicated competitive intelligence units staffed by CI professionals and headed by a Competitive Intelligence Officer. Others favored more loosely structured efforts, in some cases simply having operating departments and staff contribute information into an accessible database. Robert Galvin, the chairman of the Executive Committee of Motorola, Inc. and one of the pioneers of modern corporate competitive intelligence (Motorola's Business Intelligence system is recognized by many as the most advanced operation of its kind), listened to the discussion and then took the podium, where he spoke adamantly in favor of CI as a professionally staffed effort, with an intelligence program that is both centralized and widely disbursed throughout the company. Below, we provide an excerpt of his remarks. © 1997 John Wiley & Sons, Inc.

CEO ROUNDTABLE ON CORPORATE STRUCTURE AND MANAGEMENT INCENTIVES

CEO ROUNDTABLE ON CORPORATE STRUCTURE AND MANAGEMENT INCENTIVES