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Celebrate the Past– Invent the Future DIA 2014 50TH Annual Meeting Professional Posters June 15-19 San Diego, CA Invent the Future Celebrate the Past– DIA 2014 50TH Annual Meeting June 15-19 | San Diego, CA On Tuesday, June 17 and Wednesday, June 18 in San Diego, CA, DIA recognized ninety-one (91) professional poster presenters who presented scientific developments related to topics addressed in this year’s program. Presentations were made in conjunction with the DIA 2014 50th Annual Meeting “Celebrate the Past - Invent the Future.” Poster No. Author Poster Title Page T 01 Barbara Hendrickson, MD Development and Implementation of Product Safety Statistical Analysis Plans 6 T 02 Rachida Essalihi, PhD Ensuring Patient Recruitment Success in Phase I Clinical Trials: The Important Role of Investigators 6 T 03 Jonathan Seltzer, MD, MA, MBA, FACC Good Clinical Practice (GCP) Training: Identifying Key Elements and Strategies for Increasing Training Efficiency 6 T 04 Tracey Cannova Evaluation of Current and Future Medical Information Services Offered to Healthcare Providers by Pharmaceutical Companies 7 T 05 Nicole Turner, MBA Evaluation of Site Enrollment Estimates Pre- and Post-initiation to Actual Enrollment Performance: An Assessment of Accuracy 7 T 06 Marianne Pedersen, PhD Country-Specific Clinical Data and Reporting Requirements in Support of Marketing Applications To Key Rest-of-World Countries 7 T 07 Paul Sheehan Effectiveness of REMS Patient Education: An Assessment of Patient Comprehension and Knowledge Retention 8 T 08 Kelly Colletti, PhD, MBA Development of an ELISA Method to Characterize C1q Binding Affinity 8 T 09 Catharine Provosty Best Practices to Effectively Close a Complex, Global Study: Different Stakeholder Perspectives 8 T 10 Niki Kutac Using Gamification in the Life Science Industry 8 T 11 Elisa Cascade, MBA Burden of Clinical Trial Operations and Value of Supporting Solutions: Results from a Global Investigator Survey 9 T 12 Luann Van Campen, PhD, MA, MSc The Role of Bioethics in the Pharmaceutical Industry: Informal Review of 5-Year Trends and One Company’s Systematic Approach 9 T 13 Christine Cheng, PharmD A Survey of Boxed Warning Adverse Reaction Content from US Prescription Drug Labeling 10 T 14 Sandy Greene Processes and Responsibilities within Bioanalytical and Clinical Operations to Ensure PK Sample Management in Phase 1 Studies 10 T 15 Nicole Zandy, PhD Choosing Your Investment: What’s the Right Data Quality Solution for You? 11 T 16 Dinah Duarte, PharmD, MSc Global Regulatory View of Nonprescription Medicines Classification 11 T 17 Rachel Skelton Validation of Next Generation Sequencing Panels for Targetable Mutations in NSCLC and TNBC Using FFPEs and Liquid Biopsies. 11 T 18 Elizabeth Rach A Regulatory Informatics Approach to Identifying Trends in Minimal Residual Disease for the Hematologic Malignancies 12 T 19 Sarah White, PharmD Characterizing Medical Information Requests from Payer Customers to Improve Database Planning for Respiratory Assets 12 T 20 Penelope Manasco, MD, MS Assessing Current Monitor Performance on Monitoring Competencies for Risk Based Monitoring 13 T 21 Kelly Hageman, PharmD Utilization of Cross-Pollination Meeting Series: A Potential Catalyst for Innovation 13 T 22 Dena Cosgrove, RPh Evolution of Pharmacovigilance Regulations in the US and Europe 13 T 23 Vinit Mehta, PharmD Validation of an Internal Communications Streamlining Initiative Utilizing an External Communications Benchmarking Study 13 T 24 Libby Cerullo, MSc Electronic Investigator Site Files: The Hidden Gem that Completes Remote Risk Based Monitoring 14 Poster Abstracts | diahome.org/DIA2014 2 Invent the Future Celebrate the Past– DIA 2014 50TH Annual Meeting June 15-19 | San Diego, CA Poster No. Author Poster Title Page T 25 Michael Waddington, MS Precision Laboratory Network (PLN): PBMC Processing and Nuclei Acid Isolation Suitability Study 14 T 26 Laura Wallace, MPH Use of Epidemiology Data to Inform Pediatric Clinical Trial Design and Execution and Its Impacts on MSL Support 14 T 27 Libbie McKenzie, MD A Strategic Approach to Portfolio Benefit-Risk Assessments (BRAs) 15 T 28 David Horsburgh Avoid at Your Risk? The Potential for Naïve Sites to Rescue Failing Recruitment and Study Under-Performance 15 T 29 Kai Yu Jen The Role of Medical Writers in Preparing Responses to Post-Submission Queries From FDA, PMDA, and EMA 16 T 30 Ben Dudley The Evolution of an Enterprise Risk Based Monitoring Process 16 T 31 Dominique Johnson, PhD, MSc A Multi-Modalities Medical Imaging Investigative Network for Clinical Trials in Cardiovascular, Neurology and Oncology 16 T 32 Kim Le, PharmD Analysis of Product Labeling Changes for Successful Prescription to Over-theCounter Switches 17 T 33 Nicole Griswold Utilizing the MSL Role to Characterize the Transition of Care of Patients with Attention Deficit Hyperactivity Disorder 17 T 34 Nazia Rashid, PharmD, MS Descriptive Evaluation of REMS Knowledge in An Integrated Healthcare System 17 T 35 Kenichi Otani, PhD International Comparison of Process and Procedures to Overcome Clinical Trial Applications Placed on Clinical Hold 18 T 36 Regina Ballinger, BSN, MS, RN Impact of FDA Advisory Committee Voting on FDA Approval Decisions for Drugs and Biologics 18 T 37 Zsuzsanna Csutor The Silver Lining of the PSMF: Flow Chart Displaying the Business and User Requirements 19 T 38 Krista Payne, MEd Rock and a Hard Place: Mandated Multi-National Drug Utilization Studies in the Absence of Suitable Secondary Sources of Data 19 T 39 Kristin Palmsten, DrSc Medication Use Among Pregnant Women Enrolled in Medicaid 19 T 40 E. Mitchell Seymour, PhD, RAC eCTD Submission Capability to FDA for Academic Sponsor-Investigators: Process, Problems, and Possibilities 20 T 41 Kathy Boardman, MS Integrating ISO and Relevant Industry Standards to Improve Clinical Trial Project Management Processes 20 T 42 NaRae Baek Can Asia Help Expedite Cancer Drug Development? Analysis of Three North Asian Countries’ Potential to do More Clinical Trials 20 T 43 Bhavini Srivastava, MS Electronic Data Capture in Oncology: A Review of Electronic Collection of Patient-Reported Outcomes 21 T 44 Sally Okun, RN Patient-Informed Clinical Trials: Cross-Sectional Survey on a Patient Powered Research Network 21 T 45 Craig Burnett Delivering Quality Systems Globally 22 T 46 Karolyn Kracht, MS Creating Standard Analyses and Displays for Common Safety Assessments in Clinical Study Reports 22 W 01 Weining Robieson, PhD Evaluation of Operating Characteristics of MMRM Analysis Using All Available Longitudinal Data at Interim Compared to ANCOVA 22 W 02 Pascal Guibord, MSc Recent Developments in Scaled Average Bioequivalence 22 Poster Abstracts | diahome.org/DIA2014 3 Invent the Future Celebrate the Past– DIA 2014 50TH Annual Meeting June 15-19 | San Diego, CA Poster No. Author Poster Title Page W 03 Annette Williams, MBA, RPh An Overview of Both Current Best Available and Next Generation of Drug Therapies for the Treatment of Depression 23 W 04 Karen Lockwood Health Literacy Assessment, Usability Testing, and Revision of a European Union Risk Management Plan Public Summary 23 W 05 Bambi Grilley, RAC Coordination of a Multi-site Cell and Gene Therapy Study in an Academic Medical Center: A Success Story 23 W 06 Irene Sheng, PharmD An Innovative Way of Providing Timely Responses to Questions Related to Ingredients/Allergens 24 W 07 Esther Sadler-Williams, MPharm, MSc, RPh Evaluating and Supporting the Increasing Patient Need for Delivery of Clinical Trial Supplies Direct to Their Homes 24 W 08 Ilyssa Levins New Business Acumen Tool Guides Strategic Thinking: Learn How to Increase Your Value to the Company and to the Industry 24 W 09 Rebecca Hummel Complexity in Protocol Design: Does it Lead to Better Clinical Trial Outcomes? 25 W 10 Abhishek Harde Corporate Integrity Agreement and Its Impact on Industry 25 W 11 Ben Quartley, PhD Giving Clinical Trial Start Up A Project Management Make-Over: Reducing Cycle Times Through Critical Path Focus 25 W 12 Raul Vinueza The Impact of Regulatory Reform in Mexico on Pharmaceutical Product Approval 25 Rates W 13 Ed Seguine, MBA So How DO You implement eSource: Practical Tips for Enhancing Efficiency, Data Visibility, and Site Interactions 26 W 14 Andrew Buchanan, RPh Duloxetine Feeding Tube Study: Medical Information Example of Collaboration with Laboratory Scientists to Deliver Answers. 26 W 15 Elizabeth Nielsen Targeting the Best Sites with an Analytical Site Selection Model Using Multiple Metrics 26 W 16 Allan Spera Central Recruitment Methodologies in a Global Clinical Research Study of a Pediatric Autism Spectrum Disorder (ASD) Program 27 W 17 Mona Vimal, MSc Evaluation of Shipping Systems to Maintain Sample Integrity in Clinical Research 27 W 18 Christopher Bone A Comparison of MedDRA SMQs Relative to Individual Preferred Terms for Signal Detection on a Large Insurance Claims Database 27 W 19 John Li, MD, MBA Introducing and Conducting Traditional Chinese Medicine Trials in the US: Challenges, Obstacles, and Potential Solutions 28 W 20 Geoffrey Gipson Coherence of Observed-to-Expected Disproportionality Methods Used for Pharmacovigilance at a Critical Threshold 28 W 21 Tracey Miller Enhancing Project Management Tracking to Facilitate the Protocol Development Process 28 W 22 Christina Gallagher, PharmD Continued Tradition of Success: Critical Components of the Genzyme/Sanofi Oncology/MCPHS University Post-PharmD Fellowship 29 W 23 Phil Reveal Assessment of Violations Cited by OPDP in Untitled and Warning Letters Issued from 2004-2013 29 W 24 Jeff Jamer, MBA Accelerating Patient Recruitment Using In-Depth Market Research Insights: Collected via a 3rd Party - From Clinical Trial Site Staff 30 W 25 Penelope Manasco, MD, MS Implementing a Standard Report Set for Risk Based Monitoring Domains 30 W 26 Ayako Takizawa, MS Investigation of Association Between COPD Treatment and Cardiac Events With or Without Treatment for Co-Existing Disease 30 Poster Abstracts | diahome.org/DIA2014 4 Invent the Future Celebrate the Past– DIA 2014 50TH Annual Meeting June 15-19 | San Diego, CA Poster No. Author Poster Title Page W 27 Caroline Lin, MA Reinventing the Study Build Process to Promote Consistency, Increase Build Efficiencies, and Reduce Overall Timelines 31 W 28 Hanming Tu, MSc Collaborative Development of an Open Source Repository for Standardized Analysis Using Cloud Services 31 W 29 Toshiyoshi Tominaga Quality of Japanese Clinical Trials and Proposed Strategy for the Trial Sites 31 W 30 Gary Noel, MD A Collaboration to Facilitate the Development of Antibacterial Agents for Unmet Need: Streamlining Clinical Trial Protocols 32 W 31 Holly Groelle, PhD Global Regulatory Considerations for Biosimilar Approval 32 W 32 Alex Wei Impact of FDA Breakthrough Therapy Designation on the Regulatory Timelines of Chronic Lymphocytic Leukemia (CLL) Therapies 32 W 33 Yueqin Zhao, PhD An Extension of Likelihood Ratio Test-Based Method for Signal Detection in a Drug Class with Application to FDA’s AERS Database 33 W 34 Alun Tanner, PhD Maintaining Effective Pharmacovigilance Oversight: The Role of Remote Auditing 33 W 35 Mikhail Samsonov Data Empowered Decision Making in a Pharmaceutical Company: Project Libraries and Workflows - Real Life Experience 33 W 36 David Bristol, PhD Sample Size Re-Estimation Can Be Very Inefficient 34 W 37 Jessica Kloda, PhD So You Hired a CRO…Now What? Advancing Clinical Research by Leveraging Government Sponsor Relationships with CROs 34 W 38 Cyril Carrere, MSc Office of Prescription Drug Promotion (OPDP) Enforcement Overview From 1997 to 2013 35 W 39 Jennifer Zellner, PhD Enrollment of Pregnant Women in Medication Safety Research: MotherToBaby Pregnancy Studies 35 W 40 Badhri Srinivasan, PhD, MS A Model for Centralized Monitoring: Reducing Costs While Ensuring Compliance, Risk Mitigation and Quality 35 W 41 Barbara Del Curto Customer Satisfaction and Communication Methods Used in Conducting Large Multi-Center Clinical Trials 35 W 42 Rona Grunspan Easy as A,B,C? Adapting Pediatric Protocol Designs from Existing Adult Data and Study Templates 36 W 43 Tsung-Ta Wu The Construction and Promotion of Medication-Used Safety Education for Traditional Chinese Medicine in Taiwan 36 W 44 Jonathan Nguyen Diep Patterns of Regulatory Approval for Targeted and Immunotherapeutic Compounds Indicated for the Treatment of Metastatic Melanoma in the US and EU 36 W 45 Dara Stein, MSc Retrospective Chart Review Studies: Key Considerations for Fullfilling Safety Reporting Requirements 36 Poster Abstracts | diahome.org/DIA2014 5 DIA 2014 50TH Annual Meeting June 15-19 | San Diego, CA T 01 Development and Implementation of Product Safety Statistical Analysis Plans Barbara Hendrickson, MD AbbVie Inc. Objective: The objective was to develop a living document that specifies the approach for integrating and analyzing safety data from multiple clinical trials of a product to facilitate decision making during clinical development and to support safety discussions in regulatory submissions. Method: The creation of a standard operating procedure (SOP) describing the development of a Product Safety Statistical Analysis plan (PSSAP), as well as a PSSAP template, was a cross functional effort (Pharmacovigilance, Statistics, Clinical, Project Management, Regulatory) at AbbVie in 2013. Results: The PSSAP initiative was launched at AbbVie in 2012 with the formation of a crossfunctional working group and the initiation of two pilot projects. In 2013, an SOP and PSSAP template were implemented and trainings regarding the PSSAP were conducted. The SOP describes the procedure for developing and approving a PSSAP and documentation of the review of the PSSAP output. The PSSAP is to be created for products by Phase 2b or earlier and is the predecessor of the Integrated Summary of Safety (ISS) Statistical Analysis Plan for new product or indication filings. The PSSAP is a reference document for ongoing safety analyses throughout the product life-cycle, evolving over time. The PSSAP provides detailed instructions on how the safety data will be pooled and analyzed for safety signals, adverse events of special interest (AESI), and safety assessments of special populations. The PSSAP helps ensure the collection of appropriate data in ongoing studies to analyze AESIs. The PSSAP output supports consistent safety related discussions in regulatory submissions including the Investigator Brochure, Developmental Safety Update Report (DSUR), and ad-hoc regulatory responses. The Product Safety Teams review the PSSAP output and document the clinical assessment of the data analyses. The PSSAP is reviewed by the Product Safety Teams on at least an annual basis and is updated as needed. Conclusion: Product level safety statistical analysis plans promote proactive, systematic, and thoughtful product level safety monitoring. Aggregation of safety data from multiple studies in the pre-ISS phase enhances the ability to detect signals and make drug development decisions. The standardized PSSAP template also fosters cross-functional alignment to best practices for safety analyses, including analyses of AESI. Ongoing training regarding the value of the PSSAP is important to ensure successful implementation. Pilot projects provide useful information to advise the PSSAP initiative, as well as valuable examples for subsequent education of the product safety teams. The PSSAP is a living document that evolves over the product life cycle and informs the planning of safety data collection and consistency in the execution and quality of data analyses. Co-authors: Shihua Wen, Mondira Bhattacharya, Karine Smith, John Schoenfelder T 02 EEnsuring Patient Recruitment Success in Phase I Clinical Trials: The Important Role of Investigators Rachida Essalihi, PhD Algorithme Pharma Inc., Canada Objective: To evaluate and compare the critical involvement of different types of investigators on recruitment, screening and enrollment power of patients in early stage clinical trials. Method: Compare the patient enrollment success rate of two different physician involvment levels in two Phase I trials. The study U24 was based exclusively on patient referals while study N25 implicated an active participation of the investigator in the clinical study conduct. Results: In study U24, 12 patients were to be enrolled in the study. Although 54 patients were refered by the offsite specialist to the clinical unit, 7 patients were finally enrolled and completed the study. Additionally, 23 of the 54 patients refered attended the screening visit, signed the consent form and were subsequently screened. Of those 23, twelve (12) patients were rejected at screening and thus, 11 patients were eligible for dosing (47.83% of the total patients screened). Lastly, from the 11 eligible patients, 7 patients were enrolled and completed the trial (63.64% of the total eligible patients). As such, from the initial step, more than 57% of the patients actively interested in participating lost their interest in the trial. Considering the initial number of patients refered to the trial, 13% of the 54 patients were enrolled. The duration from the First Patient In (FPI) to Last Patient In (LPI) was 4 months, resulting in approximately 17 days per patient enrolled, although more than one subject was enrolled within the same dosing group. In study N25, 16 patients were to be enrolled. For this study, the investigator recruited patients from his own database. All interested patients were screened by the Investigator on site. Of the 23 patients screened, 6 patients were rejected and 17 patients were eligible for dosing (73.91% of the total patients screened). Sixteen (16) out of the 17 eligible patients were enrolled and completed the trial (69.57% of the total patients screened). The duration from FPI to LPI was 3 months, resulting in approximately 6 days per patient enrolled. As for study U24, more than one subject was enrolled within the same dosing group. Conclusion: Poor performance in patient recruitment and retention is known as an important reason for delays in clinical trials. Many intrinsic and extrinsic factors could impact the success of patient recruitment and enrollment. In the present case study, the impact of the motivation and involvement of an investigator was evaluated on actively recruiting and enrolling patients. As observed in study N25, from initial discussions to the screening process, the actively involved investigator was able to increase its own screening power by over 50 % as compared to the other one (study U24). Additionally, we also observe a lower screening failure rate (about 25%) which could suggest a better understanding of protocol requirements and potentially an optimization in patient identification. In fact, 73.91% of screened patients in study N25 were eligible compared to 47.83% for study U24. Finally, in regards to improvements in timelines, the actively involved investigator in study N25 had a FPI to LPI of about 3 times faster than the U24 study enrollment, a difference of 11 days per patient, even though, in Canada, more patients are affected by the disease targeted for recruitment of study U24 (1 person over 7.6 as compared to 1 person over 15 for N25). This case study clearly illustrates the synergistic impact that an actively involved investigator has on a clinical trial timeframe. Multiple other factors can be present which can also affect recruitment and enrollment power as illustrated in a previous poster presentation (Legault E., Essalihi R., Lahjou M., Paraskevopoulos H. & Lefebvre M. How a Study Design could Impact on Recruitment and Enrollment Success: A Case Study. ASCPT 2013 Annual Meeting, Indianapolis (IN , USA), 2013.)). However, an investigator’s motivation and involvement is definitively a critical factor that should not be under estimated. Co-Authors: Mira Francis, Eric Legault, Nadine Al-Hage Ali, Marc Lefebvre T 03Good Clinical Practice (GCP) Training: Identifying Key Elements and Strategies for Increasing Training Efficiency Jonathan Seltzer, MD, MA, MBA, FACC Applied Clinical Intelligence, LLC Objective: To develop recommendations to ensure knowledge of GCP while facilitating a more efficient GCP training process Method: The Clinical Trials Transformation Initiative (CTTI) convened a multidisciplinary working group involving partners from academia, industry, and government to develop recommendations for streamlining current GCP training efforts. Results: The working group reviewed the current literature and the content of public and private initiatives related to GCP training, and drafted recommendations to define the minimal key elements required for GCP training. Draft recommendations were presented to a broader group of experts from the clinical research enterprise to foster discussion on the issues, and seek consensus on proposed solutions before finalization. The recommendations that define strategies to providing more efficient training, including a frequency for repeat training, the format Poster Abstracts | diahome.org/DIA2014 6 DIA 2014 50TH Annual Meeting June 15-19 | San Diego, CA to deliver the training, and approaches for competency assessment after the training is complete will be discussed. Additional strategies on designing training programs that integrate GCP elements into clinical research will also be discussed. Conclusion: The recommendations for GCP training requirements generated through this effort may encourage organizations to adopt similar training criteria, thereby allowing cross-acceptance of training. This may serve to reduce the burden of repeated training, and improve the efficiency of clinical trials. CTTI-GCP Training Working group: Jamie Arango, Tina Chuck, Susan Ellenberg, Bridget Foltz, Colleen Gorman, Heidi Hinrichs, Susan McHale, Kunal Merchant, Stephanie Shapley, Jonathan Seltzer, Gretchen Wild T 04Evaluation of Current and Future Medical Information Services Offered to Healthcare Providers by Pharmaceutical Companies Tracey Cannova Rutgers, The State University of New Jersey Objective: To evaluate the types of medical information services offered to healthcare providers through pharmaceutical company medical information communication methods and online resources as well as evolution of medical information in the future. Method: The Rutgers Pharmaceutical Industry Medical Information fellows and fellowship alumni as well as Drug Information Specialists throughout the country were surveyed to evaluate the medical information services provided to healthcare providers, their value and thoughts of evolution. Results: The study is in progress but will be completed in advance of the meeting. Over one hundred Rutgers Pharmaceutical Industry Medical Information fellows and fellowship alumni were surveyed as well as approximately three hundred Drug Information Specialists were surveyed. Conclusion: The study is in progress but will be completed in advance of the meeting. T 05Evaluation of Site Enrollment Estimates Pre- and Post-initiation to Actual Enrollment Performance: An Assessment of Accuracy Nicole Turner, MBA Quintiles Inc. Objective: Evaluate investigator enrollment estimates made pre- and post-site initiation against actual performance to determine whether accuracy improves along the continuum of site selection; review identified trends by region/ therapeutic area, and recommend a reduction factor for use in strategic planning. Method: The enrollment estimates given by over 500 investigators globally during various stages of site selection have been compared to the actual enrollment performance of the same investigators in 5 or more studies conducted globally by Quintiles that are no longer enrolling from years 2009 to 2011. Results: The commonly held belief that investigator enrollment estimates received prior to site selection are generally optimistic in comparison to actual enrollment performance in a study is true based on our analysis; investigator estimates received prior to site selection are, on average, 75% higher than the investigators’ actual enrollment performance. Investigators indicate that this can be attributed to lack of protocol details being available, short timelines for responding, and purposeful inflation of enrollment estimates to ensure the site appears favorable for study inclusion, among other reasons. However, investigator estimates made based on full review of the protocol after the site has been selected for the study may also be poor indicators of actual performance on the study. We will evaluate if the inaccuracy seen pre-initiation persists, and if so, whether this inaccuracy is seen across indications and countries analyzed. Trends seen by indication, country and therapeutic area will be presented. Using these results, we have modeled begun an analysis using linear regression of the data overall, as well as by region and indication, in order to make recommendations for reduction factors to be applied to investigator estimates at multiple points during study enrollment planning. These reduction factors will vary based on the stage in site selection that the investigator enrollment rates were gathered. Analysis is ongoing; we are systematically reviewing recently completed studies for potential inclusion in order to continually advance our analysis and to further validate our findings. Conclusion: Basing study enrollment projections on investigator enrollment rate estimates will likely result in an inaccurate prediction of last patient in. Investigator estimates received prior to site selection are significantly overly optimistic; however, even after site selection, when investigators begin planning to conduct the study and have received a full protocol for review, they may be unable to provide an accurate (+/10%) estimate of their site’s actual enrollment performance on the study. Applying a reduction factor to these data will allow for investigator estimates to be more useful indicators of potential study enrollment; the reduced rate can be used in creating enrollment projections for a study. T 06 Country-Specific Clinical Data and Reporting Requirements in Support of Marketing Applications To Key Rest of-World Countries Marianne Pedersen, PhD Bristol-Myers Squibb Company Objective: To compare and contrast clinical documentation requirements in key Rest-ofWorld (RoW) countries that require local patient experience to inform on clinical effectiveness and extrapolation to the overall global population in support of marketing approval. Method: Regulatory guidelines were reviewed for China, Japan, Korea, Taiwan, Mexico, India, and Russia. These countries have established requirements for the inclusion of clinical data reflective of the local population in order to facilitate the review of a marketing application. Results: Countries such as China and Japan require local studies be conducted to obtain patient experience reflective of the population within those countries. These data not only provide an assessment in a particular region or ethnic population, but allow for extrapolation (or bridging) of local findings to the overall population in global studies. These data are reported in country-specific clinical study reports (CSRs) and in clinical summary documents as part of the marketing application. Other countries, such as Korea and Taiwan, require the inclusion of their local population in registrational global clinical studies for population-specific analyses and extrapolation to the overall global population. These countries require the submission of specific bridging study evaluation (BSE) reports prior to or together with the submission of their marketing application. These comprehensive BSE reports provide an overview of the pharmacology of the drug and address the potential for ethnic sensitivity of the drug being evaluated according to ICH5 guidelines. Furthermore, BSE reports provide PK/PD data for the local population as well as a comparison of efficacy and safety data between the local and global populations. Both Korea and Taiwan have specific sample size requirements of the country-specific subpopulation, but differ in the definitions of the population subsets that need to be compared in side-by-side data displays. Other countries such as Mexico, India, and Russia, like Korea and Taiwan, also require the inclusion of their local populations in key global clinical studies, but limit analyses to efficacy and safety in the local population without formal comparative analyses to global data. These data are presented in subpopulation reports submitted as part of the marketing application and are discussed within the context of findings from the global population. Conclusion: China, Japan, Korea, Taiwan, Mexico, India, and Russia represent countries with specific and different data presentation and reporting requirements for their local populations. Regulatory requirements drive the need for country-specific clinical studies or inclusion of their Poster Abstracts | diahome.org/DIA2014 7 DIA 2014 50TH Annual Meeting June 15-19 | San Diego, CA countries within key global registrational studies to provide population-specific pharmacology, safety and efficacy data. Operationally, local data to support country-specific reporting requirements as part of marketing approval in key RoW countries require early planning as well as early crossfunctional team engagement. T 07Effectiveness of REMS Patient Education: An Assessment of Patient Comprehension and Knowledge Retention Paul Sheehan Celgene Corporation Objective: To evaluate the effectiveness of patient education activities conducted within the Risk Evaluation and Mitigation Strategies (REMS) programs for lenalidomide and thalidomide from 2012-2013. Method: U.S. lenalidomide and thalidomide patients receive mandatory education about serious risks and safe-use conditions as part of comprehensive REMS programs. This study examines the execution and outcomes of these programs, via results from knowledge and behavior surveys conducted from 2012-2013. Results: During the study time period 73,645 patients participated in a mandatory survey executed just before they obtained a prescription, and of these 3,981 responded to an additional voluntary survey initiated several weeks after they received their prescription. Both surveys assessed patients understanding and compliance with key pregnancy prevention education messages delivered by their healthcare professionals before they started therapy, and repeated frequently throughout their treatment duration. Most patients were treated for Multiple Myeloma (83%), and the average age was 66. Females of reproductive potential comprised 3% of the patient population, males 55%, and females not of reproductive potential 42%. Patients completed 264,417 mandatory surveys, of which 14,848 (5%) indicated an inaccurate or uncertain understanding of safe-use messages (e.g. patient risk category assignment, appropriate pregnancy prevention measures, sharing of blood or sperm, and sharing of product). These were investigated and resolved prior to a dispense. 90% of the voluntary survey respondents confirmed receiving REMS patient education materials, and 86% having read them. Results from the survey conducted within 14 days of first dispense shows 98% understood the key safeuse messages, and the same number reported retaining this knowledge in a follow-up survey performed 3 months later. During the study time period 396,761 prescriptions were written, 5% required intervention to ensure they met REMS safe-use requirements (of which 43% were for females of reproductive potential), and 2% resulted in a delay in treatment initiation or a gap in therapy. Conclusion: Both surveys confirmed that patient education activities conducted within the lenalidomide and thalidomide REMS programs were successful. Patients reported receiving and reading the program education materials, understood the serious risk and safe-use conditions, retained this knowledge throughout therapy, and were generally compliant with safe-use conditions. The study results were fairly consistent across patient age, gender and risk category. The impact on therapy delivery of confirming and investigating if patients have received and understood key safe-use messages is reasonable. This study illustrates how safe-use educational messages delivered to patients on a consistent and repeated basis may form an important element of successful comprehensive REMS programs. Such an approach can achieve high levels of patient understanding, knowledge retention and compliance. Additional authors include Nancy Brandenburg, Dr. Robert Bwire, John Freeman, and Dr. Florence Houn who are all employees of Celgene Corporation. T 08 Development of an ELISA Method to Characterize C1q Binding Affinity Kelly Colletti, PhD, MBA Charles River Laboratories International, Inc. Objective: To characterize the effector function of monoclonal antibody biotherapeutics through the development of an immunoassay to measurethe C1q binding potential of a human IgG, which is necessary for activation of complement dependent cytotoxicity (CDC). Method: We have developed an in vitro immunoassay that characterizes the C1q binding potential of human IgG. The development involved optimizing the ELISA assay procedure and conducting statistical analysis of the data in order to determine if the assay could compare relative C1q binding affinities. Results: The basic design of the assay is to use a solid microtiter plate to immobilize the human IgG in order to allow the C1q molecule to bind to the Fc portion of the antibody. The human IgG is absorbed to the plate surface at various concentrations to produce a standard curve. The complex is then detected with an anti-C1q antibody labeled with horse radish peroxidase in a colorimetric reaction. This format allows for the comparison of C1q binding potential between similar IgG molecules with applications for in vitro characterization of biosimilar and biobetter biotherapeutics through the comparison of the standard curves. The assay was optimized with respect to coating buffer, incubation times, human IgG concentrations, and detection reagent. The optimized assay demonstrated precision as evidenced by %CV values less than 15% between curves when evaluating ED50 values. Conclusion: The immunoassay is a robust assay that is capable of comparing the C1q binding potential of human IgG based biotherapeutics. This assay could be used to compare relative binding affinities through comparison of ED50 values of various biotherapeutics with specific applications in biosimilar and biobetter biotherapeutic development programs. T 09 Best Practices to Effectively Close a Complex, Global Study: Different Stakeholder Perspectives Catharine Provosty Covance Inc. Objective: Data driven case study investigation of proactive approaches to plan and stop screening activities for a phase II complex, global study with limited over enrollment. Method: Starting in 2011, the objective was to screen, enroll and randomize 200 breast cancer patients in US, LA, EU and AP. Presenting the process flow from screening through randomization, the poster demonstrates how close communication between all stakeholders was critical to limit over enrollment. Results: Screening was closed globally, across 26 countries and four regions, within 24 hours. Site staff was very responsive to the closure as they had been kept informed of the expectations for a quick response. This poster will illustrate the approaches to achieve this result, presenting the process flow sites had to follow for screening through randomization for their patients as well as illustrate the various points a patient could screen fail. Firsthand examples will illustrate how close communication between the site staff, patient, laboratory and project management team embodied a critical best practice approach to limit over enrollment. Conclusion: A common goal in clinical trial conduct is to complete enrollment as quickly as possible, as well as minimize over enrollment to limit exposure to the study drug, avoid waste and use resources as efficiently as possible. To achieve these objectives it is necessary to gain alignment and buy in from all stakeholders from the very start of the study. These stakeholders range from staff at study sites, principal investigators, clinical team members from various organization as well as global regulatory agencies who have reviewed and approved the study for their country. Co-presenter: Annabel Vaghar, Senior Clinical Trial Manager T 10Using Gamification in the Life Science Industry Niki Kutac DATATRAK Objective: The objective of this study is to analyze the usage of Gamification during a clinical trial to incentives the clinical sites and Poster Abstracts | diahome.org/DIA2014 8 DIA 2014 50TH Annual Meeting June 15-19 | San Diego, CA study team to improve clinical trial data quality and speed of data entry. Method: For this study we reviewed the results of using Gamification in other industries & success rate of changing key behaviors & activities. We simulated the use of Gamification during the testing of a major release of an eClinical technology and the rate of closing bugs identified during the testing. Results: The results of implementing a game environment and providing a price of being “crowned” Data Hero, we experienced a 300% increase in the speed of bug closer than experienced before the Gamification was implemented. By simply implementing a game environment and identifying a winner we experienced increased at and even above what other industries experience with implementing Gamification techniques. Conclusion: Gamification can be implemented within a Life Science company in many ways to improve performance and speed: Patient Adherence, Education (from sites to CRAs), Adherence to Timelines (data entry timelines, data cleaning timelines, regulatory reporting, etc.), or Quality of Work (queries generated). Thus, it is important for an organization to properly plan and understand what they are trying to implement before undertaking a Gamification project. With implementing Gamification, organizations not only incentivize their clinical sites to improve overall response times but also provide visibility to data-driven information through better reporting and dashboards that allow sponsors to manage and evaluate the site’s quality and timelines. T 11 Burden of Clinical Trial Operations and Value of Supporting Solutions: Results from a Global Investigator Survey Elisa Cascade, MBA Drugdev.org Objective: The objective of this poster is to present the results of a global survey of 750 investigators related to the burden of clinical trial operations and the value of various support solutions. Method: Between Oct 28 and Dec 3, 2013, we emailed ~11,000 randomly selected members of the DrugDev investigator network in Argentina, Australia, Germany, India, South Africa, UK, and the US to invite them to an on-line survey of 25 questions. Respondents were offered a chance to win one of 5 ipads. Results: 750 investigators located in a study country completed the on-line survey: 98 in Argentina, 61 in Australia, 60 in Germany, 81 in India, 45 in South Africa, 66 in the UK, and 344 in the US. The overall response rate was 7% with country level response ranging from 4% (Germany) to 14% (Argentina). Of the physicians surveyed, 8.1% had participated in 2 or fewer trials, 37.7% had previously participated in 3 to 10 trials, and 54.1% had participated in more than 10 trials. Most respondents had experience in more than 1 therapy area (average of 3.5 per investigator) with the Top 4 as follows: Cardiovascular (26.8%), Internal Medicine (25.3%), Endocrinology/Diabetes (24.9%), and Pulmonary/ Respiratory (20.9%). Globally, completing contractual and regulatory documents was rated as the most burdensome administrative activity with 46% of investigators rating this as very or extremely burdensome. Getting paid on time was the second most burdensome issue (36% rated as very or extremely burdensome). At least 30% of investigators also rated the following as very or extremely burdensome: recruiting patients (32%), budgeting for clinical trials (32%), completing feasibility surveys (31%), and reporting SAEs (30%). Interacting with on-site monitors was considered the least burdensome activity evaluated in the survey (13% rated as very or extremely burdensome). Interestingly, interacting with remote monitors was relatively more burdensome (21% rated as very or extremely burdensome). With respect to supportive solutions, over 70% of global investigators found five activites extremely or very valuable: 1) Cross-pharma GCP repository with training needed once every two years (85%), 2) Ability to upload investigator CVs to a cross-pharma repository (79%), 3) Guaranteed investigator payment within 30 days (78%), 4) Annual Master Service Agreement (MSA) with cross-pharma repository of essential documents (75%), and 5) Cross-sponsor sharing of contractual preferences (73%). Conclusion: According to analyses conducted by CenterWatch, Tufts, and others using FDA 1572 data, the investigator landscape has shifted in ways that challenge successful conduct of clinical trials (e.g., fewer experienced sites; high turnover among new PIs). The resulting impact for Sponsors is higher operational costs, especially related to site identification, qualification, and start-up. The purpose of our investigator survey was to better understand sources of investigator burden in clinical trial operation and to determine the value to investigators of potentially supportive solutions. Although published literature on investigator burden in clinical trials is limited, our findings appear to be consistent with comments made by industry experts who have suggested study start-up and ethics as large sources of difficulty for investigators as well as a trend towards higher protocol complexity posing challenges to patient recruitment. Understanding the feedback on burden, it is not surprising that the supportive activities that offered the most value to investigators were items that either guaranteed payment or streamlined start-up such as GCP training, contracting, and essential document collection. Although there is no benchmark with which to compare, the level of value assigned to these activities was high in absolute terms (70%+ of the sample rated as extremely or very valuable). One additional conclusion that emerges from the study is that the supportive activities with the greatest investigator value are all operational items under the control of the pharmaceutical research sponsor. Several efforts underway have begun to address some of these solutions (e.g., Transcelerate, Investigator Databank), but it will be interesting to monitor the degree to which the pharmaceutical company research sponsors are able to change their processes to ultimately achieve the goal of reducing investigator burden while also realizing time and/or cost efficiencies. T 12 The Role of Bioethics in the Pharmaceutical Industry: Informal Review of 5-Year Trends and One Company’s Systematic Approach Luann Van Campen, PhD, MA, MSc Eli Lilly and Company Objective: The goal of this project was to assess the role of bioethics in the pharmaceutical industry as evidenced by trends from an informal review of industry practices as well as Eli Lilly and Company’s systematic approach. Of specific interest was what companies state publicly about bioethics. Method: An informal review of approximately 20 major pharmaceutical companies was conducted recurrently since 2008. The cohort changed over time as a result of mergers/acquisitions. Data from corporate websites were supplemented by other public search engine data. Results were recorded in Excel. Results: Both descriptive and qualitative initial assessements are being completed. Bioethics information assessed include: company website content, committees, full-time effort, education, projects, and publications. To date, data reveal a 45% increase in the use of the word ‘bioethics’ on company websites from 2008 to 2014. In 2008, few companies had webpages dedicated specifically to bioethics or research ethics. In 2014, there are 7. Some companies included bioethics-related material in externally-facing documents, such as corporate responsibility or investor reports. The first mention of a company bioethics committee occurred in the mid-1990’s. From 2008 to 2014, there has been approximately a 20% increase in the number of company bioethics committees – with quite varied purposes and structures. In 2008, two companies had full-time effort (the first established in 2001, the second in 2008). In 2014, a third company has established full-time effort. In 2014, 4 companies specifically mention internal bioethics education but only one delineates what is offered. Externally-facing projects have ranged from monetary donations to collaborative projects with academia and private institutions. Peer-reviewed industry-authored bioethics publications are few. In addition to the review data, Eli Lilly and Company’s systematic approach to bioethics will be shared—outlining the purpose and composition of the Bioethics Program that was established in 2008. Core activities include position development, consultation service, Poster Abstracts | diahome.org/DIA2014 9 DIA 2014 50TH Annual Meeting June 15-19 | San Diego, CA education and training, collaborative projects (both internal and external), and scholarship. Based on 5-year metrics and experience, a working definition of ‘pharmaceutical bioethics’ can be proposed, and implications for a pharmaceutical company and the industry can be discussed. Conclusion: Bioethics is a discipline that examines ethical issues of both healthcare and biomedical research. To date, the pharmaceutical industry has been criticized both for its lack of bioethics involvement and conversely for its funding (and presumed undue influence) of bioethics initiatives. The current informal review provides a perspective, albeit imperfect, on the developing role of bioethics in the industry. Since 2008, there is increasing pharmaceutical company activity and investment in this discipline, but the range of self-described activity is still unchanged—ranging from no mention of bioethics to full-time effort. Therefore, it is reasonable to conclude the role of bioethics in the pharmaceutical industry is yet undefined. The lack of consensus is not overly suprising. First, because the industry is highly regulated, it is presumable that most companies rely on regulations to provide adequate human subjects protections, and rely on ethics and compliance departments to provide ethical guardrails. However, the systematic approach and experience of one company indicate ‘pharmaceutical bioethics’ should be considered complementary to, but separate from, legal compliance. Second, the lack of consensus is not surprising because the bioethics field has yet to recognize pharmaceutical bioethics as a sub-discipline— with challenges unique to a corporate setting. We propose that pharmaceutical bioethics can and should be considered 1) a sub-discipline of bioethics, 2) an integral component of pharmaceutical R&D excellence, and 3) an integral component of corporate integrity. While it is admirable to strive for excellence and integrity, it is not realistic to expect results unless there is a more systematic approach to pharmaceutical bioethics—both for a pharmaceutical company and for the industry. Until there is such an approach, the field of bioethics likely will continue to view ‘pharmaceutical bioethics’ as an experiment, at best, and an oxymoron, at worst. Co-author: Donald G. Therasse, M.D., Eli Lilly & Company (Retired). T 13A Survey of Boxed Warning Adverse Reaction Content from US Prescription Drug Labeling Christine Cheng, PharmD First Databank, Inc Objective: To review all boxed warning (BXW) content within FDA-approved prescription drug labeling available on the National Library of Medicine Dailymed website and the FDA website between July 2013 and February 2014 and report on the categories of adverse reactions (ADRs) described within the BXWs. Method: We reviewed all prescription drug labels with BXWs on DailyMed and the FDA websites. We created drug group associations based on ingredient and, if needed, dose form, strength or drug class depending on the BXW content. We then categorized the BXW ADRs with concepts similar to SNOMED CT. Results: Between July 2013 and March 2014 we created a total of 419 BXW flexible drug groupings, of which 295 were ingredient-based, 93 were based on ingredient/dose form (e.g., testosterone transdermal gel) , 7 based on ingredient/strength (e.g., mifepristone 200 mg) and 24 based on drug class (e.g., systemic fluoroquinolones). Our hierarchical representation of BXW ADRs included 25 main categories and more than 150 subcategories. Most (n=387/419, 92%) of the drug groups had a BXW that described at least one ADR (range 1 to 10 ADR concept per drug group). Among the main ADR categories, the most prevalent was hematologic abnormalities (n=103/387, 27% of drug groups), which included toxicities such as bone marrow suppression, thrombotic disorders and hemolytic anemia. The next most common ADR categories were psychiatric disorders, e.g. suicidal ideation, abuse potential, (n=72/387, 19% of drug groups); cardiovascular disorders, e.g., congestive heart failure, capillary leak syndrome, (n = 61/387, 16% of drug groups; hepatic disorders, e.g., hepatomegaly with steatosis, peliosis hepatis, (n=58/387, 15% of drug groups); neoplasms (n=50/387, 13% of drug groups); respiratory system disorders, e.g., interstitial pneumonitis, severe bronchospasm, (n=42/387, 11% of drug groups); immune system disorders, e.g., hypersensitivity reactions, infusion reactions (n=41/387, 11%) and serious infection, e.g. progressive multifocal leukoencephalopathy, tuberculosis, (n=37/387, 10% of drug groups). Additionally, the BXW for 33/387 (9%) of drug groups referenced a restricted distribution program for the drug (e.g., TOUCH prescribing program for natalizumab). For the remaining 32 BXW drug groups without ADRs, the most prevalent clinical issues described were the need for experienced physician supervision during use of the drug (n= 16/32, 50% of drug groups) and precautions surrounding appropriate patient selection criteria for use of the drug (n= 15/32, 47%of drug groups). Conclusion: The BXW is the strongest safetyrelated warning that can appear in a US prescription drug label, and is generally reserved for serious, life-threatening adverse reactions associated with use of a particular drug. To our knowledge, this is the first report of BXW content derived from systematic review of currently available prescription drug labeling on the National Library of Medicines’ DailyMed website and the FDA website (including sites for the Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research, and Medwatch). Our study demonstrates that the majority of BXWs describe at least one serious ADR, and that BXW ADRs are diverse but can be organized into a drug- and ADR classification schema. Knowing what serious ADRs are associated with the use of certain drugs is an important step toward creating a safety plan for patients taking these drugs. Hierarchical classification schema for BXW ADRs may help facilitate appropriate clinical care of an individual patient, as well as prospective monitoring/surveillance programs for BXW drugs within a health care system. Such a knowledge base could also help with retrospective drug utilization reviews and/or assessment of the impact of safety-related interventions related to a BXW drug. We were surprised to find that a minority (less than 10 %) of BXWs solely addressed non-ADRs. However, this information may be important for defining usage criteria for a given BXW drug. Future studies should focus on the specific actions clinicians can take at critical moments in the medication use process to minimize risks associated with a BXW ADR. Further studies should also determine what actions can be taken to ensure that criteria for proper patient selection, clinician expertise and other administrative requirements are met prior to use of a BXW drug. T 14 Processes and Responsibilities within Bioanalytical and Clinical Operations to Ensure PK Sample Management in Phase 1 Studies Sandy Greene Gilead Sciences, Inc Objective: To determine the incidence of compromised pharmacokinetic (PK) samples in Phase 1clinical studies conducted in 2013 and evaluate the processes associated with PK sample management in Phase 1clinical studies Method: Phase 1 studies conducted at Gilead Sciences in 2013 were reviewed. For each study, number of sites, types of samples, processing and shipping requirements were reviewed. We evaluated the processes and roles of Bioanalytical and Clinical Operations throughout the life cycle of sample management. Results: Forty-three (43) Phase 1 studies were conducted by Gilead Sciences in 2013 at 96 sites. There were a total of 36 single site studies (Phase 1 units or investigative sites) and 7 multi-site studies. The 7 multi-site studies were conducted over 60 sites (US and international). A total of 97,678 primary (plasma and/or urine) PK samples were collected. The overall reported incidence of compromised samples was <2%. The main reasons for compromised samples include: samples received at Bioanalytical Lab (BAL) at incorrect temperature (frozen vs. ambient), mislabeling of tubes, BAL receiving empty tubes, incorrect sample collection tube utilized, and shipping logistics (e.g. package held at the vendor’s warehouse). Over all, the low incidence of compromised Poster Abstracts | diahome.org/DIA2014 10 DIA 2014 50TH Annual Meeting June 15-19 | San Diego, CA sample integrity in the studies conducted in 2013 was due to a number of factors, mainly, collaborative leadership of sample management by the Clinical and Bioanalytical leads; development of the Sample Management Manual (Manuals were found to streamline the process and communication between the various stakeholders and were pertinent training and reference points for the site personnel), development of Communication and Risk Mitigation Plans and training and timely follow up of issues. Conclusion: Clinical trials require a collaborative effort between sponsors, vendors, sites, contract research organizations and collaborators. Sample integrity can be compromised at various points of a sample life cycle: collection, processing, shipping, analysis and storage. Therefore, it is important to have clearly defined processes and roles and responsibilities between Bioanalytical and Clinical Operations to optimize PK sample management. The following strategies play an important role towards successful sample management: • Partnership: Clinical and Bioanalytical Operations provide a unified view (tracking, integration, reconciliation, and real time reporting). • Training: Structured information in the form of Manuals and Plans is instrumental in dissemination of accurate instructions. • Oversight: Direct and frequent communication between Site, Clinical and Bioanalytical Operations and the Bioanalytical Laboratory reduces variability. • Risk Assessment and Management: Identification of risks, setting up processes before the start of the study; ensures efficiency and performance predictions. • Post Issue Action: Immediate management and re-training of applicable team members in response to any issues that develop increases probability of success. Authors: Mona Vimal*, Amanda Vu*, Diana Chung*, and Sandy Greene* **Gilead Sciences, Inc T 15 Choosing Your Investment: What’s the Right Data Quality Solution for You? Nicole Zandy, PhD Quintiles Transnational Corporation Objective: This project evaluates a novel methodology for assessing the cost of poor quality of operational data, taking into account several factors including aging of data, potential impact on decision-making and source of error discovery (reactive vs. proactive.) Method: A set of Data Quality Issues (DQIs) identified in the past 3 years were used for analysis. The DQIs were classified by factors (# of data points involved, source system, age, and method of discovery) and combined with a cost model to evaluate the ROI of various approaches to improving data quality. Results: This project consisted of two phases. We first leveraged historical data around Data Quality Issues (DQIs) to develop an algorithm to estimate the cost of a DQI over time. We then applied this algorithm in a simulation that examined the use of various approaches to resolving a set of DQIs to develop recommendations on identifying the appropriate solution to a new DQI that arises. In the initial phase, we randomly selected a set of DQIs with resolutions in place. We conducted interviews with representatives from key operational groups (e.g. Clinical Site Monitoring, Data Management, Central Laboratory) to identify factors that may modify the cost of resolving a DQI. These included the overall number of data points involved, error rate, source system characteristics (number of end users, other systems that use this data,) method of discovery (reported by an end user in the business or proactively identified as a potential issue) and time. To determine cost, we used a modified version of the 1-10-100 rule as stated by SiriusDecisions: “It takes $1 to verify a record as it’s entered, $10 to cleanse and de-dupe it and $100 if nothing is done, as the ramifications of the mistakes are felt over and over again.” After refining the data quality cost algorithm, we applied the algorithm to a second set of DQIs to simulate the ROI of different approaches available to resolve the issue and prevent its occurrence in the future. These results were then extrapolated to design a decision matrix that can be applied to determine which approach to recommend for a specific DQI. For example, in some cases, requiring a field in CTMS is the best approach; in other instances, mandatory field may prevent a CRA from completing a site visit report and a data alert is appropriate. In addition, this data allowed us to extrapolate factors that can be used to justify the business decision to invest in technology to verify records in near real-time vs. a process for data cleaning vs. inaction. Conclusion: Transforming the way the health care industry brings new medicines to the patients who need them in the most cost-effective manner requires us to harness the power of both patient data and operational study management data. In fact, the most recent FDA guidance on risk-based monitoring (RBM) suggests that a well-designed, clearly written protocol and the ability to leverage technology to monitor site and data quality are critical components for successful study delivery using a RBM plan. However, technological advances that offer the promise of data-driven insights are only as good as the data feeding those systems. As such, ensuring the quality of that data is paramount to realizing the full value of these systems. The perceived difficulty of measuring the intrinsic value of high quality data often prevents firms from attempting to do so. This, in turn, often leads to inaction or misdirected action to improve data quality because of the inability to measure success or justify a business investment in a data quality initiative. Our empirical research demonstrates that a relatively simple model can be derived to monetize the value of data quality, which is commonly thought of as a nebulous concept. Further, we have identified a number of factors that can be assessed to help guide decisionmaking with regard to implementing a proactive solution to ensure data is clean upon entering a system or taking a reactive solution to correct/ complete data after a lag period. On the other hand, it may not always make sense to invest time or technology in fixing the data, e.g. there is not much value in correcting enrollment data from RA studies conducted 10 years ago because the standard of care has changed so dramatically. Finally, this model can be used to evaluate the ROI of investing in a technological solution to automate the process of data correction. T 16Global Regulatory View of Nonprescription Medicines Classification Dinah Duarte, PharmD, MSc INFARMED, Portugal Objective: To address issues concerning the legal status of medicines in a global way and the switch strategy implemented in Portugal (The Portuguese 3rd List)). Method: We propose to cover the following areas: • Legal status of medicinal products in the marketing authorisation (MA) • Assessing the reclassification procedures and identifying potential areas for improvement • Innovative non-prescription medicines in the centralized procedure Results: We intend to present the regulatory and policy environment impacting self-care and the critical role that healthcare professionals can play in realising the self-care potential, by addressing how to appropriately respond to the public health and citizens’ needs for innovation and access to effective and safe products of high quality. Conclusion: This Portuguese exercise in switch reveals that our country is a strong believer in patient empowerment and a wider access to healthcare and intends to facilitate high-quality, effective and safe products reaching citizens. T 17 Validation of Next Generation Sequencing Panels for Targetable Mutations in NSCLC and TNBC Using FFPEs and Liquid Biopsies. Rachel Skelton Insight Genetics Inc. Objective: To establish procedures to validate Next Generation Sequencing assays for clinical laboratory adoption using formalin fixed paraffin embedded specimens and matched blood samples focusing on a targeted NSCLC panel and an algorithm-driven RNAseq-based TNBC assay. Method: Validation was conducted using a compartmentalized approach that validated the instrument, nucleic acid extraction, assay protocol, and bioinformatics as separate entities. Poster Abstracts | diahome.org/DIA2014 11 DIA 2014 50TH Annual Meeting June 15-19 | San Diego, CA NGS panels were run on the Illumina miSeq instrument. A minimum of 32 specimens were tested in replicate sequencing runs. Results: Validation of the non-small cell lung cancer (NSCLC) and triple-negative breast cancer (TNBC) assays determined the accuracy, precision, analytical sensitivity, analytical specificity, reportable, and reference range of each component of the NGS procedure. Validation of the Illumina miSeq was performed using the PhiX Control v3 library and analysis of the base call accuracy, sequence read agreement, and coverage depth. All assays were validated for the corresponding nucleic acid extraction protocol used i.e., DNA, RNA, or Circulating Nucleic Acid. The targeted NSCLC panel utilizes the Illumina TruSeq® Custom Amplicon design. This comprehensive panel identifies the key mechanisms of ALK inhibitor resistance. Samples of known mutation status were run in replicate and evaluated based on an average amplicon coverage > 500X. The targeted NSCLC panel protocol was adapted to survey circulating nucleic acids from plasma or serum for efficient monitoring of ALKspecific or secondary drivers of drug resistance from patient blood. Matched solid tumor samples were utilized when available to confirm detection of tumor-derived nucleic acid. The mean target coverage across all exonic regions was between 4000X- 20,000X, significantly higher than the generally accepted 500x coverage. Validation of the bioinformatics pipeline established that the targeted NSCLC panel showed a sensitivity of 94.3%; specificity of 100% and limit of detection of > 6.5% mutant content. The TNBC diagnostic assay is designed to target a poor-prognosis population to provide guidance for treatment with the most effective therapeutics based on expression profiles. For this format of assay, RNAseq validation was performed with matched fresh-frozen and FFPE specimens. RNAseq data was analyzed using a software algorithm and compared to previously acquired microarray data to classify TNBC patient samples into subtypes responsive to targeted therapies. Conclusion: The utility of Next Generation Sequencing in clinical laboratories depends on the development of sequencing panels that focus on clinically actionable oncogenic drivers. Strict procedural guidelines for clinical validation of NGS assays are not currently in place; thus, it is critical that clinical laboratories take care to robustly validate lab-developed NGS tests. All assays presented in this work have been validated using guidance from CLIA, CAP, and New York State certification bodies and show > 90% sensitivity and specificity. Compartmentalized validation simplifies future assay validation in that validation is only required for process components differing from currently validated processes. The targeted NSCLC panel allows for detection of the precise resistance mechanism(s) operative in an individual patient’s tumor which can guide physicians in tailoring decisions for the selection of second-line therapy or appropriate clinical trials. Because second biopsies from diseaseprogressing patients is not standard practice, the targeted NSCLC panel was validated for a non-invasive method using blood samples to allow for continuous monitoring of a patient’s inhibitor resistance profile. Validation robustness was ensured using patient specimens of known mutations status or comparing matched solid tumor and blood specimens. A second NGS assay described in this work functions to better characterize TNBC samples into clinically targetable subtypes. RNAseq followed by a software algorithm analysis provides physicians with clinically relevant genetic information to help improve treatment options and selection for this group of cancer patients. Validation robustness was accomplished by comparing data outputs from the TNBC NGS assay to matched microarray data. In summary, these NGS assays have been robustly validated and are available for use in the clinical setting. T 18A Regulatory Informatics Approach to Identifying Trends in Minimal Residual Disease for the Hematologic Malignancies Elizabeth Rach Janssen R&D, LLC Objective: Minimal residual disease (MRD) holds great potential to allow for earlier detection of relapse, accelerated approval, and shorter trial duration. We aim to assess utilization of MRD across efficacy endpoints, hematologic malignancies, technologies, and the development of breakthrough therapy drugs. Method: We performed advanced searches in the Clinicaltrials.gov Registry (dated 30 January 2014) and analyzed the results using ActivePerl (v5.12.2) and R (v2.13.0). The numbers of clinical trials for efficacy endpoints, indications, and technologies were assessed using trial start dates or cumulative sums. Results: There were 262 clinical trials returned with the search terms “minimal residual disease” or “major molecular response” in the Clinicaltrials. gov Registry, each trial having 24 properties. The growth in utilization of progression-free survival (PFS), overall survival (OS), event-free survival (EFS), and MRD showed that PFS and OS had the highest growth rates, while EFS and PFS showed similar profiles until they diverged in 2007. The first trial reported in the registry using MRD was recorded in 1995 and since then, a trend of positive growth has been observed. The utilization of MRD was evaluated across hematologic malignancies and were classified into 3 categories based on their prevalence in the Clinicaltrials.gov Registry, as follows: MRD as an established endpoint (ALL, CML), MRD as an emerging endpoint (AML, CLL), and MRD as a novel endpoint (DLBCL, FL, MCL, MM, WM). Next, the prevalence of the technologies PCR, FISH, flow cytometry, and sequencing was evaluated for the hematologic malignancies and MRD, over time and cumulatively. Both registry analyses showed that PCR (114 cumulative trials) was the most predominant technology, followed by flow cytometry (31 cumulative trials), FISH (10 cumulative trials), and sequencing (2 cumulative trials). This reflects the overall trends observed for the usage of technologies over time and cumulatively across endpoints in the hematologic malignancies. Lastly, investigational drug development programs with breakthrough therapy designation were evaluated for their incorporation of MRD. As of 03 January 2014, Friends of Cancer Research reported 28 drugs with public disclosure of breakthrough therapy designation; 6 of which were granted for hematologic malignancies. Results showed that 4 (66.7%) out of the 6 had at least one trial utilizing MRD and ofatumumab had the highest number of trials using MRD (7 trials). Conclusion: The application of regulatory informatics to the Clinicaltrials.gov registry data is a novel approach to identifying trends across efficacy endpoints and characterizing utilization of MRD. These results show that MRD is an emerging efficacy endpoint in the evaluation of hematologic malignancies. As technologies continue to advance to enable more precise detection, the role and context of MRD in regulatory strategy will continue to evolve. Elizabeth A Rach1*, Shruti Kalra1*, Hsiao-Ling Hung*, Terri Williams* 1 These authors contributed equally to this work. *Department of Oncology Global Regulatory Affairs. Janssen Research & Development, LLC, 920 US Highway 202, Raritan, NJ 08869. T 19 Characterizing Medical Information Requests from Payer Customers to Improve Database Planning for Respiratory Assets Sarah White, PharmD GlaxoSmithKline Objective: The primary objectives of this study are to develop an understanding of medical information (MI) requests from payer customers beyond the AMCP Dossier and to improve the ability of MI scientists and field liaisons to prepare for and respond to payer inquiries. Method: This retrospective database review will focus on payer requests for information submitted directly to Medical Information or via scientific engagement request forms (SERFs) between January 1 and December 31, 2013. Results: In order to identify topics of frequent interest to payers at various phases of a product lifecycle, trends in the numbers and types of requests for newly approved products, older assets and above-brand topics within the respiratory space will be documented. Fulfillment modes for each request will be classified into one or more of the following categories: verbal response, MI response, publication, scientific Poster Abstracts | diahome.org/DIA2014 12 DIA 2014 50TH Annual Meeting June 15-19 | San Diego, CA presentation, literature search, and AMCP dossier. Ultimately, this information will be used to characterize MI resource utilization for frequently asked questions and to create a process for database planning in this space. Data have been collected and final results are to be presented at the conference. Conclusion: Conclusions are pending analysis. T 20Assessing Current Monitor Performance on Monitoring Competencies for Risk Based Monitoring Penelope Manasco, MD, MS MANA Consulting Objective: The objective of this abstract is to provide monitoring competencies for Risk Based Monitoring and the results of a national skills assessment provided to current monitors. Method: Risk Based Monitoring has significantly changed the role of the monitor. We developed a set of monitoring competencies through dialog with experts in the industry. We developed a skills assessment based on these competencies and distributed it to staff performing monitoring on clinical trials. Results: A set of questions based on each competency was used. These questions included skills assessment for interpreting data from graphs and tables and other report formats that are part of risk based monitoring. Monitors were asked multiple questions for each competency and then a final score was provided for each competency. This presentation will provide data on which competencies had the most monitor proficiency and those with the least proficiency. The results will show the results for each competency for monitors based on the number of years they have been functioning as a monitor. Conclusion: A thorough assessment of current monitor training needs is required to facilitate the transition from traditional monitoring to risk based monitoring. This poster provides monitoring competencies for Risk Based Monitoring, examples of assessment questionnaires, and highlights the areas where most monitors will need additional training. T 21Utilization of Cross-Pollination Meeting Series: A Potential Catalyst for Innovation Kelly Hageman, PharmD MCPHS University School of Pharmacy Objective: The MCPHS University Fellows’ Network (MFN, comprised of more than 40 fellows and alumni across 7 functional areas and 5 pharmaceutical companies) piloted a quarterly cross-pollination meeting series in an effort to capitalize on the potential benefits of crossfunctional collaboration. Method: The meeting series was designed as a quarterly 90-minute Industry Seminar, each focusing on one functional area within the pharmaceutical industry. Each seminar consisted of formal presentations and two round-table discussions. Surveys were used to measure the value and utility of each meeting. Results: To date, two Industry Seminar events have been developed and executed with a total of 46 participants (n=28 and n=18, respectively) in attendance; 40 completed the post-meeting survey (n=24 and n=16, respectively). The events hosted participants from 5 functional areas within the biopharmaceutical industry including: clinical supplies, translational medicine/clinical research, medical affairs, pharmacovigilance, and regulatory affairs. Overall, 95% of fellows strongly agreed (n=29) or agreed (n=9) that the seminar series was educational and worthwhile. All fellows strongly agreed (n=31) or agreed (n=9) that each event was an excellent opportunity to learn about co-fellows working in different departments. Ninety percent of fellows strongly agreed (n=23) or agreed (n=13) that the Industry Seminar provided them with an in-depth understanding of other functional areas in the biopharmaceutical industry. Via free text on the surveys, fellows expressed an appreciation for gaining an enhanced understanding of the roles and responsibilities beyond their own departments as well as the differences between companies. Overall, 97.5% of fellows strongly agreed (n=29) or agreed (n=10) that they learned something new about the biopharmaceutical industry during these events. Conclusion: MFN designed a cross-pollination meeting series in an effort to utilize the functional diversity present within the network, further cultivate individuals’ knowledge of various roles within the biopharmaceutical industry, and capitalize on the potential future benefits of cross-functional collaboration. Survey results showed that the majority of fellows found the MFN Industry Seminar series to be valuable and beneficial in creating an opportunity to learn about different functional areas. Although there were a limited number of events, the program’s aim of cross-pollination and enhancement of understanding across departments was reached. Through this seminar series, fellows gained exposure to different viewpoints, which will likely foster future collaboration and innovation within participants’ own functional and cross-functional teams. T 22Evolution of Pharmacovigilance Regulations in the US and Europe Dena Cosgrove, RPh Quintiles Transnational Corporation Objective: This poster will examine the history of pharmacovigilance, identifying key turning points and likely future developments. Method: Milestones in the evolution of pharmacovigilance will be identified, with an analysis of trends in adverse event reporting in the United States and Europe. Results: A review of legislation will be presented, starting with the first UK law aimed at regulating drugs, the Pharmacy Act of 1868, and the United States’ 1902 Biologics Control Act and 1938 Federal Food, Drug and Cosmetic Act. Key milestones such as the thalidomide tragedy in the 1960s will be examined. The poster will provide information on drug safety activities at national and regional regulatory authorities, the World Health Organization and the International Conference on Harmonization. The author will highlight the trend for safety monitoring to move from passive approaches (spontaneous adverse event reporting) to more reactive (action in response to interventions by regulators) and proactive methods (using electronic medical records [EMRs] and risk management programs such as Risk Evaluation and Mitigation Strategies [REMS]). The impact of the Prescription Drug User Fee Act will also be discussed. Conclusion: Pharmacovigilance remains a very young science, at an early stage in its evolution. Looking forward, increasingly proactive approaches will be required, and in future these will encompass the need to access EMR and other large data sets to identify and validate safety signals. Pharmacovigilance executives everywhere need to prepare for this. T 23 Validation of an Internal Communications Streamlining Initiative Utilizing an External Communications Benchmarking Study Vinit Mehta, PharmD Novo Nordisk Inc. Objective: The objective of this study is to identify inefficiencies in standard communication channels and methods used by pharmaceutical companies and compare the data generated against process improvements implemented in an internal communications streamlining initiative. Method: For this study, a web-based survey was disseminated to US pharmaceutical industry employees within Medical Affairs departments. Concurrently, a centralized communications solution was piloted to prioritize and distribute information to the internal Medical Affairs team during a six month period. Results: The external survey generated 184 initial responses, of which 138 met the qualification criteria of being an employee of a Medical Affairs department at their respective pharmaceutical company. Of the eligible 138 responses, 119 completed the survey yielding an 86.2% completion rate. Questions included in this survey were based on factors such as unclear messaging and prioritization, information overload, actionable items, and time allocations. Similar measurements were used in the internal pilot that was conducted using roughly one-fourth (36 members) of the Medical Affairs team. At the conclusion of the six month pilot period, 80% of participants reported that the pilot program Poster Abstracts | diahome.org/DIA2014 13 DIA 2014 50TH Annual Meeting June 15-19 | San Diego, CA addressed the underlying inefficiencies of interdepartmental communications. Participants reported a 29% decrease in individual email volume and a 98% increase in centralized intranet usage leading to an average of 18 hours saved across the team per week on communication channels. While time saved on communications may seem minor, this pilot was only conducted using a small subset of the department over a short period of time. It did not take into account information disseminated by members outside of the pilot group. Furthermore, with the centrallized communications solution relaying a clear understanding of responsibilities and level of prioritization, 100% of the participants met the time-sensitive deadlines. Conclusion: This study shows that across all pharmaceutical companies, there are core inefficiencies in communications that mirror what is seen within our Medical Affairs department. Factors such as repetition, redundancy, and lack of prioritization all negatively impact productivity. Our internal metrics showed that by implementing a central communications solution, improvements were made for not only one, but all inefficiencies listed above. When these improvements were taken into account, there was a combined reduction in time spent managing information. By prioritizing communications and clarifying actionable items, users had more guidance on short- and long-term deliverables, which led to increased participation and completion rates. Overall, this communication streamlining project has allowed for strategic alignment across a National field-based medical team and a clear vision across the internal and external medical affairs organization. The outcomes of this pilot program have resulted in the launch of national implementation internally. The concept behind this initiative could be applied to any company looking to increase productivity and improve their communication processes. I want to acknowledge my co-author for this abstract, Samantha Yang. T 24Electronic Investigator Site Files: The Hidden Gem that Completes Remote Risk Based Monitoring Libby Cerullo, MSc Pivotal Consulting LLC Objective: The objective of this abstract is to highlight the importance of transitioning site document management from paper regulatory binders to electronic Investigator Site Files to enhance efficiency and to facilitate Risk Based Monitoring. Method: We implemented electronic Investigator Site Files that were available electronically to the Site, the Sponsor, and the CRO. This enabled remote review and reconciliation of trial documents independent of the site visit. There was no paper maintained for the study at all. Results: We will present data on the time to review documents, elimination of onsite monitoring visits, use as a component of Risk Based Monitoring, the acceptance of the site(s) to using electronic Investigator Site Files, and time to close out for the eTMF and electronic Investigator Site Files. We will show how we used the DIA reference model for investigator Site Files in our processes. We will also provide data on the use of a dynamic site essential document checklist to assure inclusion of all documents at the Site and Sponsor Level. Conclusion: The Electronic Investigator Site File provides a key component of risk based monitoring and is critical to remote oversight of investigative sites. We provide examples of how we developed our processes to take full advantage of the electronic investigator site files. We further provide actual implementation metrics and practical aspects to enhance implementation. T 25 Precision Laboratory Network (PLN): PBMC Processing and Nuclei Acid Isolation Suitability Study Michael Waddington, MS Precision Bioservices, Inc Objective: The Precision Laboratory Network provides an integrated network of global laboratories following the same procedures with demonstrated comparable results for PBMC isolation and DNA and RNA extraction. Method: Multiple laboratories in the PLN processed fresh human blood to isolate PBMC which were all tested for recovery, viability and functionality. In addition, DNA and RNA were isolated from PBMC and tested for yield and quality. Procedures were performed using reagents available to all laboratories. Results: Matched fresh blood samples were processed by different laboratories witihin the PLN. All laboratories followed the same procedures to isolate and cryopreserve the PBMC. The post-thaw recovery and viability of the cells from all laboratories was substantially similar. In addition, functionality as measured by IFN-g ELISpot assay revealed that cells from all laboratories retained matching functionality after isolation and cryopreservation. DNA was isolated from matched fresh and frozen PBMC at different laboratories. Both fresh and frozen PBMC yield comparable amounts of DNA. The purity was measured by OD260/280 and all laboratories produced DNA that met our acceptance criteria of 1.6-2.0. RNA was isolated at multiple laboratories from fresh PBMC or PBMC frozen in RNAlater to preserve RNA activity during the freezing process. The RNA was isolated following the same procedure and using kits that are available worldwide. The resulting RNA showed similar yield and purity by 260/280, with all laboratories providing RNA between 1.8 and 2.0. RNA integrity, as measured using the RIN, was over 7 for all laboratories. Conclusion: This Suitability Study demonstrates that multiple laboratories, widely separated by geography, can coordinate to provide matched sample processing. By following identical procedures, using reagents available in all locations, and performing periodic suitability studies across the network, the PLN provides worldwide assurance that research or clinical trial samples from widely separated locations are processed to produce comparable data. This assurance allows sponsors to have confidence in the utility and comparability of results achieved from all sites in a multi-center trial, accelerating drug and vaccine development. T 26Use of Epidemiology Data to Inform Pediatric Clinical Trial Design and Execution and Its Impacts on MSL Support Laura Wallace, MPH Purdue Pharma L.P. Objective: Our objective was to demonstrate the use of epidemiology studies to provide targeted, population-specific data to enhance a pediatric clinical trial (CT) program, with focused efforts for CT site and investigator identification, feasibility assessment, and Medical Science Liaison (MSL) support. Method: We conducted an epidemiology study of pediatric pain patient characteristics and treatment. These data informed CT design, recruitment, and regulatory interactions. We collected feedback on the data’s usefulness for improving trial participation and subject enrollment from MSLs and other CT staff. Results: This study included data on 25.5 million pediatric patients from throughout the US. Of these children, 1% had orthopedic conditions associated with pain, 1.8% malignancies, 0.3% surgeries, 3.5% trauma, and 0.7% genetic conditions associated with pain; 8.7% of all pediatric patients had a specific pain diagnosis. Diagnoses varied by age, with most showing higher prevalence in older children (age 12-16). Treatments evaluated included NSAIDS, COX-2 inhibitors, opioids (IR or ER), antidepressants, topical analgesics, anticonvulsants, and other therapies. Treatment varied substantially by condition, and many children, particularly in younger age groups (age 0-5 and 6-11), did not receive any prescription pain treatments (>50% for most of the conditions evaluated). Overall, IR opioids were used in 17.7% of pediatric patients with pain conditions, compared to ER opioids in 0.1%, NSAIDS in 7.5%, antidepressants in 4.0%, anticonvulsants in 2.0%, topical treatments in 1.4% and glucocorticoids in 4.9%. The types, doses, and duration of treatments varied substantially by condition and patient age, with the highest prevalence of pharmaceutical use in older children. We used these data to inform decisions about trial design, investigator and site selection, and MSL support. Findings enhanced MSL/ investigator interaction through clinical discussions of painful conditions and treatments. A targeted initiative for surgical and orthopedic Poster Abstracts | diahome.org/DIA2014 14 DIA 2014 50TH Annual Meeting June 15-19 | San Diego, CA populations was implemented to expand subject recruitment efforts, based on data showing the relatively high prevalence of children requiring pain treatment at study-relevant doses and timeframes within these populations. Activities to identify additional practitioners involved in pain management were undertaken based on study data. Study data contributed to identification of specialty centers and physicians for site selection. Epidemiology data combined with existing CT enrollment data to further understanding of site enrollment potential. Conclusion: With a broad range of potential investigators crossing multiple specialty areas and practice settings, identification of clinical trial sites for a study of pediatric pain can be challenging. By targeting efforts based on targeted prevalence and patient characterization data from epidemiology studies, sites may be evaluated in greater detail considering physician’s specialty focus, areas of clinical interest, and actual patient populations. Feasibility assessments may be augmented based by evaluating the site’s patient populations compared to prevalence data and protocol inclusion/exclusion criteria. MSL support of clinical trials includes initial site identification, as well as support of investigators and site staff with protocol education and discussion of potential patient populations. Data collected from epidemiological studies provides the MSL with clinically relevant evidence to provide investigators with tools to enhance subject recruitment or to engage in outreach efforts to additional clinical specialties. Overall, MSL support of clinical trial sites was strengthened through education based on study findings about pediatric conditions associated with pain and treatments utilized for such conditions. MSL education and targeted, epidemiology-data-driven initiatives contributed to improved site support and clinical discussions with investigators. Engaging patient advocacy organizations may contribute to increased awareness and improved patient recruitment efforts for pediatric clinical trials. The prevalence data obtained in our study provides a comprehensive list of conditions that may include pain comorbidities. Many of these conditions have associated patient advocacy organizations, and outreach to these organizations has shown to expand clinical trial awareness. T 27A Strategic Approach to Portfolio Benefit-Risk Assessments (BRAs) Libbie McKenzie, MD Quintiles Inc. Objective: Given that sometimes several hundreds of products within a specific portfolio are selected for a benefit risk assessment Quintiles objective was to develop a streamlined approach on how to achieve this goal within a short time frame. Method: Quintiles leveraged the processes and structures established by its Safety Aggregate Reporting and Analysis group and other expertise to develop a streamlined approach for clients. Different models of delivery had been compared and evaluated taking dependencies and efficiencies into account. Results: Key factors driving the success of this project include: • Selection and prioritization of molecules The pre-selection of drugs for which the BRA is desired resulted in >300 drugs to assess from a benefit risk perspective in a six-month period. A possible strategy to prioritize was to divide the portfolio in therapeutic areas (TAs) and to assign MDs and other specialists with experience in a certain TA to the drugs concerned. This approach created synergies for the various products within a given TA. • Depth of review The review of documents which served as the basis for each BRA started with the most recent PSUR/PBRER, the CCSI, and the RMP if available. For all active ingredients as a further prerequisite, it was necessary to identify important risks and to assess the status of signals for the evaluation of potential risks. Furthermore, a literature search focusing on systematic reviews and metaanalyses was performed. Clinical Guidelines for respective indications were considered. • Process for high through-put, short-term delivery Logistics were critical for both an efficient and reliable high quality delivery of a large volume of documents and for economic reasons. All contributing disciplines were clearly defined in advance. The high level process of document creation was specified in writing and the individual workload for specific tasks was estimated for each contributor. The resulting working model in agreement with the client led to an assembly line approach with high through-put constant delivery of BRAs. • Further considerations A communication plan was established to facilitate the process of constant delivery over time with a built in process of continuous improvement. A time table was necessary to adhere to the processes defined and to ensure complete exchange of documents and data within specified intervals. Conclusion: This was an innovative project and one with multiple future implications with lessons learned. For instance, it was considered essential to first perform a pilot phase with each client who is dealing with high volumes of BRAs to clarify upfront potential challenges and to fine tune processes with the aim to meet expectations from both parties. Interdisciplinary contributions from various functions were necessary to complete the various BRAs in a timely manner, drawing upon relevant expertise across Quintiles departments and geographies. A categorization of complexity of BRAs was undertaken, e.g., standard, medium and complex, based on several factors including: number of active ingredients, number of indications, important risks etc., with the aim of being able to estimate total working hours for a given BRA. This would allow for capacity planning in total (working hours and FTEs), but also to decide what should be done by whom, and when and how processes were intertwined. Process adjustments or fine tuning were conducted along the way. This approach provides a model of how to deliver a large number of benefit risk assessments in a short period of time and could be replicated for clients in the future. T 28Avoid at Your Risk? The Potential for Naïve Sites to Rescue Failing Recruitment and Study UnderPerformance David Horsburgh Quintiles East Asia Pte Ltd, Singapore Objective: This investigation looked at determining relative site performance across different levels of site experience; with the main aim being to assess the recruitment potential of naïve sites against the often favored experienced site pool. Method: Enrollment performance on Asia studies was assessed for this investigation. Asian sites taking part in these studies were retrospectively grouped (top, middle, low performers and naive) as they would have been at the time of study start; and median enrollment rates calculated for each tier. Results: Fourteen studies involving Asia Pacific countries were identified from the internal database with a start date between 2010-2013 All studies and included sites had at least 1 year of recruitment performance recorded • 5 therapeutic areas were covered including oncology, rheumatology, endocrinology, CNS, and cardiovascular. • Site groups were calculated specifically for each indication and was based on the following: o Past enrollment performance o Previous start-up timelines o Number of previous protocols in that indication (experience) Site groups were also calculated retrospectively to be correct at time of study start (i.e. pre-2010 data was used for 2010 studies, pre-2011 data only was used for 2011 studies, and so on) • Median rates across all studies indicated a 295% increase in enrollment rate (patients per site per month) for historically top performing sites over historic under performers • Naïve sites outperformed the historic underperformers by a median value of 157% Conclusion: Identifying high recruiting and performing sites is one of the most crucial, yet Poster Abstracts | diahome.org/DIA2014 15 DIA 2014 50TH Annual Meeting June 15-19 | San Diego, CA also the most challenging stages of the clinical trial process. Approximately 50% of initiated sites globally fail to reach their enrollment targets, with 11% failing to enroll a single patient, creating a huge patient need on the few top performing sites which becomes more and more difficult to meet. Reducing the risk of under-performers has typically involved a focus on previously-utilized sites over naïve sites with the assumption that experience working with previous protocols will reduce the chances of poor enrollment and provide a better return on the heavy investment for site start-up. However, this data shows that not only do inexperienced (naïve) sites recruit at a faster rate than poorer performing experienced sites, but they are often comparable in performance to the mid-level sites that form the majority of the experienced site pool. Key to meeting enrollment targets is not only identifying a number of key top performing sites, but also minimizing the patient deficit caused by non-enrollers or under-performers. Despite current trends in site-selection, initiating the right naïve sites to replace experienced underperformers could reduce this benefit and tip the balance back in the favour of on-time study delivery. T 29 The Role of Medical Writers in Preparing Responses to Post Submission Queries From FDA, PMDA, and EMA Kai Yu Jen Biogen Idec Inc. Objective: The purpose of this presentation is to describe the role of medical writers in preparing responses to post-submission queries from the United States Food and Drug Administration (FDA), the Japanese Pharmaceuticals and Medical Devices Agency (PMDA), and the European Medicines Agency (EMA). Method: Compare and contrast the medical writer’s experience in preparing responses to post submission queries from the FDA, PMDA, and EMA. Different approaches and styles across the regulatory agencies will be discussed in this presentation. Results: The medical writing role in preparing responses to queries from regulators includes establishing review timelines, drafting response text and tracking the status of the responses through the review process. Although the application review process differs across the FDA, PMDA, and EMA, the role of the medical writer in preparing post-submission queries from the 3 agencies is generally similar. A common approach to facilitate preparing responses to regulatory queries across the 3 agencies involves the creation of a Response Team (RT), which should include members from the following departments: regulatory affairs, clinical, safety/ pharmacovigilance, biostatistics, programming, preclinical, chemistry manufacturing and controls, pharmacology, pharmacokinetics, labeling, and medical writing. The goal of the RT is to reach consensus across the functions on the strategy for responding to the queries. For the FDA and PMDA, queries can arrive at any time after the marketing application is submitted. For both of these agencies, the review timelines are characteristically very tight (e.g., 14 to 21 days). In contrast, the EMA follows a highly structured process where regulatory queries are provided to the sponsor and the sponsor’s responses are submitted to the agency at pre-specified time points. This structured process with the EMA allows the RT to systematically plan out the strategy for addressing the agency’s queries. For all 3 agencies, the queries can range from simple requests for clarification to complex questions requiring additional analyses. Conclusion: From the medical writing standpoint, the main lessons that are relevant across all regions are: establish review timelines; track the status of the responses through the review process; remain singularly focused on the specific question; and ensure consistency across all submission documents. The main lessons that are specific to the regions are: For the FDA, ensure adequate staff to manage short turnaround timelines and never submit new data not included in the original application unless specifically requested by the regulator; for the PMDA, pay strict attention to the details of the content, always build extra time in the review process for translation; and as with FDA, ensure adequate resources to manage short turnaround timelines; and for the EMA, use the structured application review process to your advantage in planning your responses; take time to review the agency’s assessment reports, which provide context for the questions and building the responses. Co-authors: Terry Martin, Elizabeth Miller T 30 The Evolution of an Enterprise Risk Based Monitoring Process Ben Dudley Covance Inc., United Kingdom Objective: To describe the evolution of an enterprise RBM process from the baseline problem across clinical trial conduct, the processes implemented, and the data-backed outcomes achieved. Method: Over the past 5 years a global crossfunctional group (including clinical study teams, functional leaders, and expert working groups) has collaborated to define and implement an enterprise RBM process. Results: This poster will provide real life evidence data from the conduct of global clinical trials using an enterprise risk based monitoring process that has delivered quantifiable benefits in a range of areas, including: • Increased early identification of issues at the highest risk sites • Ability to provide qualitative assessment of site compliance • Increased efficiency resulting in reduced study delivery costs • Improved data flow cycle times while reducing data cleaning resource requirements Conclusion: Five years ago, there was absolute reliance on individual monitor capability to identify and resolve site issues in a find and fix paradigm. This process was prone to individual CRA failure and did not identify and manage cross study risks and trends effectively. It was hypothesized that designing and implementing processes that would maximize up-front risk identification, design monitoring interventions, and track actual performance using data and risk indicators would simultaneously drive improvements in quality and deliver efficiency benefits. A sequence of improvements were designed – implementation of a predictive, proactive and preventative study delivery paradigm, designing of site quality risk reports, an enhanced clinical quality control program, and adaptive monitoring designs all drove improvements. These formed the cornerstone of an enterprise RBM approach which was validated with the release of FDA Risk Based Monitoring guidance. T 31A Multi-Modalities Medical Imaging Investigative Network for Clinical Trials in Cardiovascular, Neurology and Oncology Dominique Johnson, PhD, MSc Montreal Health Innovations Coordinating Centre (MHICC), Canada Objective: To link together hundreds of worldwide vascular imaging experts and clinical research infrastructure and allow for unprecedented cross sectional and longitudinal clinical studies in cardiovascular, neurology and oncology. Method: A unique repository of anonymized multi-modalities medical images and medical data dispatched in real time, to the appropriate imaging core laboratory in several locations in North America to be utilized both in clinical trials and for training purposes. Results: Two Canadian national clinical research networks, CAIN (Canadian Atherosclerosis Imaging Network) and MITNEC (Medical Imaging Trial NEtwork of Canada), were created at the Montreal Heart Institute and Montreal Health Innovations Coordinating Centre (MHICC) to address the objectives of moving innovations in medical imaging toward their broad application in clinical research and facilitating the uptake of research outcomes into clinical practice and improved patient care. The MHICC plays the role of the sole coordinating centre and repository for this network. The main result of putting together these networks has been the launch of 8 major Poster Abstracts | diahome.org/DIA2014 16 DIA 2014 50TH Annual Meeting June 15-19 | San Diego, CA international multi center clinical trials with medical imaging components. The electronic exam transfer allowed by this infrastructure is essential to some of the studies because of the sensitive time component to confirm patients’ eligibility. Utilizing the CD/DVD method as was current practice would have made it impossible to get the images from recuiting clinical sites in Asia, Europe, USA and Canada to confirm patient eligibility in an acute study. Using this unique imaging network and infrastructure, more than 500 clinical sites in more than 15 countries in North America, Europe and Asia, were provided secure and private image management that included anonymization of image data and the secure transfer of image and clinical data to the data center and multi-modalities imaging core laboratories from the recruiting hospitals. The members of these networks are now engaged on a long term basis with the MHICC since this organisation is now the unique repository of the clinical research data (medical images and medical data) of the clinical trials conducted by these networks. Conclusion: Medical imaging is one of the approaches that will contribute substantially to the revolution in clinical trials leading to shorter, less expensive trials and more predictive medical benefits. Consequently, these two networks of partners and collaborators are active members of the research programs, in particular because the MHICC has developed a unique expertise in hosting significant imaging repository and transfer for multi-imaging modalities. This infrastructure allows professionals with simple, yet comprehensive access to cutting-edge research as well as providing research training and mentorship. Medical imaging expertise and infrastructure linked in this procedure allows health professionals to form a core clinical research network. Patients are recruited from qualified sites across the country, in actual time, to enable the progression of cross sectional and longitudinal clinical studies. This unique procedure assures secure image processing that includes anonymization of image data and would enable large population imaging studies. Its broad application in clinical research allows to facilitate the uptake of research outcomes into clinical practice and improve patient care. Over the last few years with the pan-Canadian CAIN and MITNEC networks, the MHICC also developed a unique expertise in hosting significant imaging repository from multi-imaging modalities, including the development and establishment of an electronic images transfer through a secure network connectivity from more than 500 remote clinical sites located in 15 countries. Additional author: Jean-Claude Tardif, MD. T 32Analysis of Product Labeling Changes for Successful Prescription to Over the-Counter Switches Kim Le, PharmD Rutgers Pharmaceutical Industry Fellowship Program Objective: The objective of this study is to identify labeling changes for medications that have had marketing status changes from prescription to over-the-counter, thereby characterizing successful switches. developed that are specifically geared toward an individual with ADHD. Both groups offered suggestions for opportunities to improve the transition process. Method: The Rx package inserts and OTC labels for first-in-class switches will be compared based on factors related to indications, dosage and administration, and safety information. A series of binary response questions will be generated for each factor. A descriptive analysis of the data will be reported Conclusion: The MSL team was able to characterize the state of transition of care for ADHD patients moving from adolescence to adulthood through in depth real time discussions with various care providers. Overall these findings highlight the need for additional education on the importance of transition of care planning, the timing and content of such discussions and the need for associated resources designed specifically for those with ADHD. Utilizing the MSL team to conduct systematic interviews resulted in the elucidation of an unmet patient need to further direct medical strategy. Additionally, these discussions have the potential to stimulate the development of tools and/ or programs designed to empower patients, caregivers and HCPs to take a proactive approach to transition planning. While this process was applied to a specific unmet need in ADHD, it has the potential to be translated across multiple therapeutic areas. Second Author: Meena Ramachandra T 33Utilizing the MSL Role to Characterize the Transition of Care of Patients with Attention Deficit Hyperactivity Disorder Nicole Griswold Shire Pharmaceuticals Objective: Transitioning care during the period of adolescence to adulthood is challenging for those with ADHD. This initiative maximized the MSL function to obtain structured feedback to identify barriers and potential best practices for the transition of care of patients with ADHD across the US. Method: From July-October 2013, the MSLs conducted interviews with health care practitioners (HCPs) who treat ADHD and with ADHD patient advocacy representatives. Information collected included demographics, knowledge of available services, barriers to transition and recommendations for these individuals. Results: Forty-seven HCPs (Adult Psychiatry =2, Child/ Adolescent Psychiatry= 16, General Psychiatry= 12, Pediatricians=2, Developmental Pediatricians = 3, Pediatric Neurologist=1, Nurse Practitioner =1) and 10 Advocacy Representatives (7 representing CHAAD) were interviewed across twenty-four states. Results suggest that although there is a lot of interest in proper transition of care, there was a significant lack of consistency in implementation of any approach. Forty-six percent (11/24) of adolescent HCPs had a specific plan or routine practice to approach transition discussions, 25% (6/24) knew discussions were necessary but did not have a plan and 29% (7/24) approached the topic on a case by case basis. Of the adult HCPs interviewed, 96% stated they were not aware of specific transition plans available, despite acknowledging the importance of these discussions. Barriers identified to the transition of care of ADHD individuals included patient understanding of the disorder, access to a health care provider educated in the treatment of ADHD, insurance issues, patients’ ability to identify support and accommodations at colleges, as well as lack of structure and caregiver support. Most HCPs and advocacy representatives could not identify specific transition of care tools or resources and acknowledged that resources need to be T 34 Descriptive Evaluation of REMS Knowledge in An Integrated Healthcare System Nazia Rashid, PharmD, MS Kaiser Permanente Southern California Objective: To assess provider perceptions and experience with REMS in an integrated healthcare delivery system. Method: Cross-sectional online survey link was emailed to eligible healthcare providers. Providers were eligible if they prescribed at least one selected REMS-related medication from 1/1/2013 to 6/30/2013. Descriptive analysis was conducted for the physicians whom completed the survey. Results: The survey focused on provider opinions about REMS, their interactions with patients, and uses of REMS materials in their daily practice. 364 respondents (34%) completed the online survey. The majority were primary care prescribers (65%), other respondents included specialists (15%), oncologists (8%), surgeons (7%) and pain management (6%). Overall, 21% of physicians felt REMS was meaningful, 41% felt it was somewhat meaningful, and 38% did not find them meaningful. Similar responses were found when providers were asked if REMS improved patient safety. When asked about providing REMS medication guides to patients, only 15% of physicians responded affirmatively; large differences were seen between the different specialty groups from 0% of pain management to 46% of oncology providers. A majority of the physicians counseled their patients or had another health care team member discuss the risks and benefits of the medications. Lastly, 48 % of respondents felt that REMS had no impact on their interactions with patients, while 39% felt that REMS had moderate impact on their interactions with patients. Poster Abstracts | diahome.org/DIA2014 17 DIA 2014 50TH Annual Meeting June 15-19 | San Diego, CA Conclusion: The results from the survey suggest that small percentage of providers (21%) felt REMS were meaningful, a small percentage (15%) provided REMS medication guides to patients and the majority (87%) felt it has little impact on their interactions with patients. T 35International Comparison of Process and Procedures to Overcome Clinical Trial Applications Placed on Clinical Hold Kenichi Otani, PhD Sunovion Pharmaceiticals Inc. Objective: The objective of this study is to compare process and procedures to overcome first-in-human clinical trial applications that were placed on clinical hold or grounds for nonacceptance in the US and the UK, respectively, as a case study. Method: Clinical Trial Applications for firstin-human studies for two, orally administered molecules were submitted (Compound A: investigation new drug application(IND), Compound B: clinical trial authorisation(CTA)). Both were denied and the processes from denial to the “may-proceed” status are compared. Results: Compound A: The IND to the FDA was placed on “clinical hold” 30 days after the submission. The removal of the clinical hold was contingent upon adopting a stopping criterion based on one tenth of the plasma concentration of the active substance and its metabolite at the level of the no-effect dose from a nonclinical study with the most sensitive species for a drug plasma concentration in the first-in-human study. Overall, the entire process (IND submission to “may proceed letter”) required 97 days. Subsequently, the stopping criterion was reached and a meeting request was submitted to the FDA to discuss removal of the cap and raising the stopping criterion. The subsequent process to escalate the dose required additional 205 days from the first dose (hit the cap) to the agreement with the FDA. Compound B: The CTA to the Medicine and Healthcare products Regulatory Agency (MHRA) was placed on “notice of ground for nonacceptance and right to amend request” 10 days after the submission. The removal of the notice of ground was contingent upon adopting a stopping criterion based on a no-observed-adverse-effect level (NOAEL) of the active substance form a nonclinical study with the most sensitive species for a drug plasma concentration in the first-inhuman study. The stopping criterion was set up to the same plasma concentration as the NOAEL. Overall, the entire process (CTA submission to “notice of acceptance”) required 30. Subsequently, the stopping criterion was reached and another meeting request was submitted to the MHRA to discuss removal of the cap and raising the stopping criterion. The subsequent process to escalate the dose required additional 14 days from the first dose (hit the cap) to the agreement with the MHRA. Conclusion: While Compound A and B are chemically distinct, the first-in-human studies for these orally administered, small compounds were not able to proceed following the initial review of the clinical trial applications. In both instances, the Health Authority required the implementation of stopping criteria based on plasma concentration from the most sensitive species in non-clinical studies in order to proceed with the clinical study. These examples highlight the International Health Authority procedural and process differences associated with removing clinical holds, specifically between the United States and United Kingdom. The process in the United States is more formal and time consuming, while the process in the United Kingdom is more informal and less time consuming. Drug Regulatory Affairs managers can utilize this information when advising teams on country selection regarding a first-in-human study, considering the difference between the MHRA and the FDA regarding the process and procedures related to clinical hold removal for an initial clinical trial application. T 36Impact of FDA Advisory Committee Voting on FDA Approval Decisions for Drugs and Biologics Regina Ballinger, BSN, MS, RN Thomson Reuters Objective: To examine voting patterns of FDA advisory committees charged with reviewing drug and biologic products under consideration by the FDA for marketing approval and relate the outcomes of these reviews to FDA’s marketing approval decisions. Method: Using committee meeting reports from 2002 to 2013, and computer analysis, committee voting was compared with FDA approval decisions. Committee support was defined as a majority vote of “Yes.” Committee rejection was defined as a majority vote of “No” or an “Equal” vote. Results: Of the 307* products reviewed by 21 committees from 2002 to 2013, 74.6% (229/307) received FDA marketing approval. Committee votes were positive in 80.8% of the cases; of the 78 products that were not approved, 64.1% received negative committee votes. Original new drug applications (NDAs) and biologics license applications (BLAs) accounted for 77.3% (177/229) and 76.9%% (60/78), respectively, of approved and not-approved products. Committee votes regarding original NDAs and BLAs were measured in cases of FDA approval: 80.2% (142/ 177) positive; 10.7% (19/ 177) negative; 9% (16/177) had no approval-related vote. Of all products* that received marketing approval in the 10-year period, 54.1% (124/229) had been granted expedited review by the FDA. The advisory committees supported 84.2% of products with priority review designation (96/114) and 85.7% for those with orphan designation (12/14). Of all products that were denied marketing approval, 42.3% (33/78) had been granted expedited review (26 priority review designations, 7 orphan designations). The committee did not offer support in 69.2% and 85.7% of the priority review and orphan cases, respectively. The 4 most active committees accounted for 43.6% (134/307) of all the products reviewed by committees for which the FDA has communicated an approval decision. Of the 229 products that have received marketing approval, these 4 committees assessed the application in 41.5% (95/229) of cases; their vote was positive 82.1% of the time. Also, they accounted for 56.4% (44/78) of products that were not approved, voting negatively 70.5% of the time. The busiest committee was the Oncologic Drugs Advisory Committee (ODAC). In cases where FDA marketing approval followed an advisory committee review, ODAC voted in the positive 85.7% of the time; when approval was denied by the FDA, ODAC had rejected support 94.4% of the time (*186 NDAs, 51 BLAs, 51 supplemental NDAs (sNDAs), and 19 sBLAs). Conclusion: Data regarding the 307 products reviewed from 2002 to 2013 appear to show a correlation between both the positive and negative committee votes and a subsequent FDA approval/non-approval. For products where the FDA ultimately granted marketing approvals, the committee had also expressed support in over three-fourths of all cases. In cases where the FDA issued a communication rejecting the application, the committee had also rejected support in 64.1% of cases. When assessed by review type (6-month review clock), a similar percentage of products that earned committee support also received FDA marketing approval. Expedited review accounts for a little more than half of all products approved by the FDA following an advisory committee meeting. For products with an orphan designation, the FDA agreed with the assessment by committees supporting the application more than 85% of the time. In cases where the FDA denied approval for orphan products, the committees had also rejected the product 85.7% of the time. Voting trends of the 4 most active committees were analyzed in more detail. About 19% of the committees accounts for 44% of overall meeting activity where product applications are concerned. These results also reinforce the overall conclusion that committee voting is predictive of the FDA’s final decision on a marketing application following an advisory committee review. Assessment of the Oncologic Drugs Advisory Committee (ODAC), the most active of all the committees, provides a specific example of the power of committee recommendations. ODAC’s vote was positive in 85.7% of the cases where the FDA granted marketing approval. This is slightly higher than the agreement rate of all committees. Poster Abstracts | diahome.org/DIA2014 18 DIA 2014 50TH Annual Meeting June 15-19 | San Diego, CA T 37 The Silver Lining of the PSMF: Flow Chart Displaying the Business and User Requirements Zsuzsanna Csutor B&C Consulting AG, Switzerland Objective: Objective: Flow chart of the PSMF processing displays the business and user requirements in accordance with the new legal requirement in EU (Dir.2010/84/EU), described in Module II guideline for a Pharmacovigilance System Master File (PSMF) since July 2012. Method: Method: Mapping, the information to be included in the PSMF per Module II in a flow chart, gives an overview to the European Medicines Agency (EMA), Competent Authorities (CA), Market Authorization Holders (MAHs) of the business and user requirement across functions within Pharma Industry. Results: Results: The primary benefit of the PSMF concept over the Detailed Description of the Pharmacovigilance System (DDPS) was seen as the reduction in the burdensome and duplicative work practices. In one glance, the flow chart of the PSMF facilitates to comprehend the massive impact of the new legislation on the working environment of the Pharma Industry displaying the potential benefits and the tremendous opportunities for the various users. Conclusion: Conclusion: The new legislation was felt far beyond the boundaries of the European Economic Area and left many breathless and weak. However the silver lining of the new legislation for PSMF was a new tool ” check my pulse” system that presented the Pharma Industry with more transparency not only to the EMA and other CAs but also positioned the MAH and QPPV in the “full knowing”. T 38 Rock and a Hard Place: Mandated Multi-National Drug Utilization Studies in the Absence of Suitable Secondary Sources of Data Krista Payne, MEd UBC, Canada Objective: Describe new evidence requirement challenges imposed by regulators with respect to evaluations of drug safety post-market; Discuss logistical challenges and timeline constraints associated with chart review DUS to inform dialogue and negotiations with regulators. Method: Increasingly, regulators are mandating multi-national drug utilization studies (DUS) to evaluate (in)appropriate use of medicines. Frequently, however,databases are lacking for all or some countries of interest. Retrospective chart studies can fill these gaps but are associated with significant operational and logistical challenges resulting in higher study execution costs and extended timelines for study sponsors. Design and operational parameters of recent chart review studies of drug utilization and safety conducted in Canada, the United States and Europe have been summarized. Opportunities, challenges and lessons learned are delineated. Results: All studies fulfilled post marketing requirements. Sample sizes varied from 100 patients to more than 2000 and the number of countries and sites varied from 1-5 and 12-375. Across studies, key design challenges included the delineation of eligibility and study periods that permitted evaluations of recent care patterns while maintaining sufficient follow-up time; determination of site-specific sampling frame methodologies to minimize selection bias; methods to minimize Hawthorn Effect and physician response bias; and safety reporting in the context of retrospective chart data. Operationally, challenges included the need for rapid study start-up to achieve site and patient enrollment, data collection and analytics within the timelines mandated by regulators. Conclusion: Sponsors must be prepared to evaluate patterns of drug utilization and (in) appropriate use even in the absence of health care databases. Though challenging to implement, retrospective chart reviews may be employed to meet evidence requirements. Knowledge of the significant design and operational and timeline challenges associated with chart review DUS is warranted to support early and constructive dialogue with regulators during study planning negotiations. T 39 Medication Use Among Pregnant Women Enrolled in Medicaid Kristin Palmsten, DrSc University of California San Diego Objective: To compare prevalences of the most commonly used or dispensed medications during pregnancy, as described in the literature, with prevalences of the same medications among pregnant women enrolled in Medicaid, the health insurance program for low-income individuals in the US, during similar years. Method: The study included 1,106,757 pregnant women enrolled in Medicaid during 2000-2007. We identified dispensing claims for medications used by >1.5% of women in the 1st trimester or by >3% during pregnancy in previous studies, excluding estrogens, progesterone, and progestins. Results: Of the 17 selected medications, nitrofurantoin 22%, amoxicillin 18%, azithromycin 17%, metronidazole-oral only 15%, promethazine 14%, cephalexin 13%, acetaminophen/codeine 11%, terconazole-topical/vaginal only 10%, albuterol 8%, terbutaline 3%, ondansetron 3%, and erythromycin-oral only 2% were the most commonly dispensed medications during pregnancy, and promethazine 8%, amoxicillin 7%, nitrofurantoin 7%, azithromycin 6%, cephalexin 4%, metronidazole-oral only 4%, albuterol 4%, acetaminophen/codeine 3%, terconazole- topical/ vaginal only 2%, ondansetron 2%, loratadine 1%, and sertraline 1% were the most commonly dispensed medications during the 1st trimester. For comparison, Andrade et al* reported the following prevalences for medication dispensings anytime during pregnancy: nitrofurantoin 7%, amoxicillin 18%, azithromycin 3%, metronidazole 6%, promethazine 4%, cephalexin 5%, acetaminophen/codeine 5%, terconazole 4%, albuterol 5%, terbutaline 4%, and erythromycin 5%. Mitchell et al** and Thorpe et al^ reported the following prevalences for medication use in the 1st trimester: promethazine 1-3%, amoxicillin 3-4%, nitrofurantoin 1%, azithromycin 1-2%, cephalexin 1%, albuterol 2-5%, acetaminophen/ codeine 1%, ondansetron 1-3%, loratadine 1-2%, and sertraline 1-2%. Levothyroxine (1% during pregnancy and 0.8% during the 1st trimester) was less commonly used than in previous studies (2% during pregnancy and 1-4% during the 1st trimester). Only 33 women had dispensings for clomiphene in the 1st trimester and 1-2% reported using the medication in the 1st trimester in previous studies. *Am J Obstet Gynecol. 2004; 191:398-407. **Am J Obstet Gynecol. 2011;205:51.e1-8. ^Pharmacoepidemiol Drug Saf. 2013;22:1013-8. Conclusion: This is the first description of commonly used prescription medications during pregnancy from nationwide Medicaid data. Previous descriptions of the most commonly used prescription medications (i.e., not focusing on specific classes) among pregnant women in the US were based on maternal self-report after delivery from volunteer-based studies (The National Birth Defects Prevention Study and The Slone Epidemiology Center Birth Defects Study) and on claims information from private insurance databases (The HMO Research Network). Medication use during pregnancy is common in the Medicaid population and prevalences of use differ from previous studies. Some of these differences may be attributable to the younger maternal age distribution in the Medicaid population (median age is 23). Antibiotics, promethazine, acetaminophen/codeine, and terconazole were commonly used in the Medicaid population and appeared to be more common than in previous studies. Lower levothyroxine use in this population may reflect under-diagnosis or lower prevalence of hypothyroidism. Clomiphene is not reimbursed by Medicaid, so use is likely underestimated in this study. Differences in prevalences may be partially attributed to the inclusion of certain routes of administration and drug combinations in some studies but not others. On one hand, we relied on drug dispensing records rather than actual use and may overestimate use. On the other hand, studies based on maternal recall may underestimate use, especially for specific medications (e.g., unspecified antibiotics vs. amoxicillin). Despite the differences, antimicrobial/antibiotic, antiemetic, analgesic, asthma/allergy, and antidepressant medication use was common during pregnancy in this study and in previous studies. Identification of medications that are commonly used by pregnant women enrolled in Medicaid but have not been identified in previous Poster Abstracts | diahome.org/DIA2014 19 DIA 2014 50TH Annual Meeting June 15-19 | San Diego, CA populations is warranted to inform priorities for studies of medication safety during pregnancy. T 40 eCTD Submission Capability to FDA for Academic Sponsor-Investigators: Process, Problems, and Possibilities E. Mitchell Seymour, PhD, RAC University of Michigan Medical School Objective: We describe the acquisition of eCTD capability within an academic medical center. We present both pros and cons from the perspectives of academia, FDA, and industry. Information includes obstacles to eCTD adoption and operational metrics to support a business case for eCTD transition. Method: This project was conducted at a regulatory unit with 30+ IND/IDE submissions and over 150 lifecycle submissions per year. Metrics include labor and/or materials costs for eSubrelated document formatting, PDF remediation, publishing (printing vs. eCTD assembly), and materials and shipping costs. Results: Sage Templates were used for MS Word document authoring, Adobe PDF Maker was used for PDF rendering, ISI Toolbox Pharma and PDF Studio 8 were used for PDF remediation, LORENZ docuBridge ONE was used for eCTD assembly and publishing, and LORENZ eValidator was used for validation. Metrics compared the paper vs. eSubmission cost of lifecycle maintenance submissions - an IND Annual Report and an IND Amendment. Results confirm that for IND lifecyle maintenance submissions, both labor and materials costs favor the adoption of eCTD capability in an academic environment. The use of MS Word templates to author eCTD-compliant PDFs is a critical component of the efficiencies gained by electronic submissions. Conclusion: To our knowledge, our institution is the first academic unit to establish internal eCTD submission capability for all of their IND Sponsor-Investigators. Electronic submissions can improve resource utilization for academic clinical research. However, given the wide range in quality and content provided by academic study teams, significant medical writing effort is needed to unify document formatting and to build eSubmission-compatible documents. As such, eSubmission-compatible MS Word templates formatted to create compliant PDF files are critical for eSub-related efficiencies. One or two staff should be designated as the regulatory publishers to maintain the unique skill sets and expertise. High-volume academic regulatory units like the one described here are equivalent to big pharma in submission activity; eSubs can yield operational benefits for managing a large portfolio and for advancing medical innovation. In an academic environment, lower cost and scalable eCTD publishing and validation solutions like LORENZ docuBridge ONE and LORENZ eValidator are required to justify the initial eSub transition, which may be slow and of lower volume. These tools are also ideal for small business, freelancers, and consultants who need an affordable and scalable publishing solution. Finally, we predict that alignment with industry submission practices will favorably impact our interactions with both FDA and industry and will enhance academicindustry partnerships. Other authors: Antoinette Azevedo, Bill Reisdorph, Jeanne Wright, Mona Moore, and Kevin Weatherwax. T 41Integrating ISO and Relevant Industry Standards to Improve Clinical Trial Project Management Processes Kathy Boardman, MS VA Cooperative Studies Program Objective: The objective of this work is to integrate ISO and relevant industry standards to improve clinical trial project management processes by developing a synergistic framework that supports the demands of large multicenter clinical trials research while aligning with quality management processes. Method: We evaluated the use of ISO and relevant industry standards in our organization’s project management and quality management systems to improve upon our processes and to harmonize multiple standards to create a synergistic framework that improves our study design and management processes. Results: The results of the evaluation by the VA Cooperative Studies Program Clinical Research Pharmacy Coordinating Center on how to harmonize ISO 21500:2012 project management requirements with ISO 9001:2008 quality management requirements identified two key elements needed for synergistic results: (1) Increase visibility and alignment with the organization’s Work Breakdown Structure (WBS) used in project scheduling and cost management processes and (2) Increased awareness of Clinical Trial Pharmaceutical Project Management as a key process in both project and quality management systems along with the other key processes essential for service/product delivery. The synergistic results included a Quality Management System based on multiple ISO standards that is transparent to the user, an increased visibility of using the Work Breakdown Structure as a framework for project management and quality management activities, and increased focused on developing a project management competency framework to assure consistency in processes and services. The organization’s quality and project management cultures now have synergistic rather than competitive alignment, leading to an overall improvement of the Pharmacy Coordinating Center’s Clinical Trial Project Management Processes. Conclusion: The results of the evaluation by the VA Cooperative Studies Program Clinical Research Pharmacy Coordinating Center on how to harmonize ISO 21500:2012 project management requirements with ISO 9001:2008 quality management requirements identified two key elements needed for synergistic results: (1) Increase visibility and alignment with the organization’s Work Breakdown Structure (WBS) used in project scheduling and cost management processes and (2) Increased awareness of Clinical Trial Pharmaceutical Project Management as a key process in both project and quality management systems along with the other key processes essential for service/product delivery. The synergistic results included a Quality Management System based on multiple ISO standards that is transparent to the user, an increased visibility of using the Work Breakdown Structure as a framework for project management and quality management activities, and increased focused on developing a project management competency framework to assure consistency in processes and services. The organization’s quality and project management cultures now have synergistic rather than competitive alignment, leading to an overall improvement of the Pharmacy Coordinating Center’s Clinical Trial Project Management Processes. T 42 Can Asia Help Expedite Cancer Drug Development? Analysis of Three North Asian Countries’ Potential to do More Clinical Trials NaRae Baek Quintiles Transnational Korea Co., Ltd, Republic of Korea Objective: To determine if there is a disparity among the incidence of a cancer, clinical trials being conducted and the drug pipeline To assess the availability of clinical trial sites for the cancers that show significant untapped patient pool for clinical trials in Taiwan, South Korea and Japan. Method: Data mining: Clinical Trial Intelligence Database, Quintiles internal and publically available data.Analysis of Cancer incidence; no. of recruiting clinical trials currently; no. of molecules in the oncology drug pipeline; available clinical trial site pool in the countries. Results: Country: Cancer; Incidence rates(ASR); No. of multi country clinical trials; No of single country clinical trials: Taiwan: Breast; 62.38; 30; 0/ Lung; 32.17;57;0/ Colorectal; 37.55; 6, 0 S. Korea: Breast; 52.1; 20; 26/ Lung; 47.1; 29; 37/ Colorectal; 69.5; 8, 34 Japan: Breast; 51.5; 12; 165/ Lung; 24.6; 30; 318/ Colorectal; 32.2; 8, 235 France: Breast; 104.5; 33; 17/ Lung; 63.1; 80; 27/ Colorectal; 64.3; 30; 25 U. S: Breast; 92.9; 56; 342/ Lung; 67.8; 101; 225/ Colorectal; 42.5; 45; 135 Incidence Number: Lung 1,824,224; Breast 1,676,332; Colorectal 1,360,056 Site approved for clinical trials; sites with capability/experience in oncology trials; top sites based on location and patient pool: Taiwan:74;35;22 S.Korea:164;74;26 Japan:7,806;168;34 Conclusion: Colorectal, breast and lung cancer are the leading cancers globally and also show a significant presence in North Asia. When Poster Abstracts | diahome.org/DIA2014 20 DIA 2014 50TH Annual Meeting June 15-19 | San Diego, CA comparing incidence rate (Age Standardized Rate -ASR) and the clinical trial landscape within a country, the number of CRC studies in S. Korea & Taiwan is very low even though the incidence rate for CRC is either higher or relatively close to other cancers. In Japan & S Korea, a significant portion of the clinical trials seem to be single country trials, most likely due to a large number of local drugs being developed and in early testing or the small number of global trials conducted in these countries being seem as ‘insufficient global experience’. When compared to a mature market like the U.S, the US shows a lot of on-going clinical trials, but mainly single country trials, which could potentially mean a lot of early phase testing. Assessment of the available site pool shows more than 100 oncology sites with capabilities across S Korea and Taiwan alone, 48 with ‘good’ capabilities based on location and large patient pool. Given the disparity in the incidence rate, no of clinical trials and huge site pool to tap into, South Korea can potentially triple the number of clinical trials, Taiwan even quadruple and Japan too can take on more trials in CRC and contribute significantly to global CRC drug development. The potential for Breast and Lung cancer trials to grow also remains strong in the region. Taiwan, South Korea and Japan can also play a potentially big part in the new trials that will emerge from the drugs currently in Phase 1 & Phase 2 development within the 3 countries itself. Given the similarities in the ethnicity and the acceptability of data by regulators in the three countries, they could play a bigger role in the clinical development of each local drug pipelines. T 43Electronic Data Capture in Oncology: A Review of Electronic Collection of Patient-Reported Outcomes Bhavini Srivastava, MS Novartis Pharmaceuticals Corporation Objective: The objective of this review is to describe the feasibility of electronic patient reported outcomes (ePROs) in studies and in clinics in oncology settings, as well as investigate potential benefits and challenges of using ePROs in oncology clinical trials, by reviewing published studies. Method: A targeted literature review was conducted in Medline using a combination of the following keywords: ePROs, electronic PROs, patient reported outcomes, EORTC, FACT, and cancer, oncology, chemotherapy, and outcomes. Search was restricted to full text articles published in English, in 2000-2012. Results: The search yielded a total of 90 hits, out of which 19 abstracts were related to ePRO use in oncology. A total of 9 full text articles were included in the review, which described benefits, as well as, challenges of using ePROs in oncology trials. Seven publications described the feasibility and acceptability, patient preferences and advantages of ePROs in oncology settings. Three of these studies compared the mode of equivalence between ePRO and paper PROs, where PRO measures such as the FACT-G, EQ5D, and the MDASI were used. Results from these studies showed that there was no significant difference in patient scores between the two modes of PRO data collection. Furthermore, the studies demonstrated greater patient acceptability, ease of administration, and ease of response in cancer patients using ePROs. One study showed that ePROs were useful in post-operative at home symptom monitoring settings. One publication demonstrated that ePROs were feasible and acceptable to patients in clinic settings. Another study demonstrated the electronic data collection method of collecting PROs as a feasible method in patients recovering from surgery due to gynecologic cancer. One study showed that ePROs are useful in collecting symptom and quality of life data in breast cancer patients. Devices used to capture data electronically in these studies included tablets, e-diaries and smart phones. Demonstrated benefits of using ePROs (reported in 7 studies) included reduction of missing or inaccurate information, increased accuracy of data capture, meeting regulatory recommendations for obtaining label claims, allowing data to remain confidential, and real time monitoring of patients for safety. Challenges of using this technology, according to study results reported in two publications, included increased training efforts for site personnel and patients, and higher system set up costs compared to paper PROs. Conclusion: The results of this review identified the growing use of ePROs in a variety of settings for oncology patients. The studies identified in this review demonstrated that ePRO technology offers distinct advantages, such as meeting regulatory recommendations, ease of administration, patient acceptability, increased accuracy of data capture, and mitigation of issues such as missing data, and concerns with confidentiality, which are common with paper based PRO collection/administration. T 44 Patient-Informed Clinical Trials: Cross Sectional Survey on a Patient Powered Research Network Sally Okun, RN PatientsLikeMe Inc. Objective: To understand motivations, barriers, and opportunities to enhance clinical trial recruitment for patients with chronic disease through a patient powered research network. Method: In February 2014, 6,819 recently active patients on PatientsLikeMe were invited to complete a survey. Over two weeks, complete responses were obtained from 1,621 patients with MS, Parkinson’s, fibromyalgia, ALS, type 2 diabetes, epilepsy, rheumatoid arthritis, depression, and lupus. Results: Only 496 (31%) could recall being invited to take part in a trial of any kind. Of these, 222 (45%) enrolled, took part and completed the study. 82 (17%) were enrolled and taking part at the time of the survey. 93 (19%) were ineligible and 57 (12%) declined to take part. About one in six patients (16%) “trial completers” who had either enrolled or were still in a trial had considered dropping out at some point. Reasons included burdensome protocols, side effects, time commitments, and financial reasons. Using the Net Promoter Score, amongst trial completers only around 57% would recommend that trial to another patient and 13% would actively dissuade others from taking part. Across all participants the major drivers of interest in a given trial were the opportunity to improve their own health (84% rated as very important), having their medical bills covered if injured (84%), the reputation of researchers involved (76%), the potential to improve the health of others (74%), and getting the results back after the trial had ended (73%). Factors listed as less important included issues that are commonly held to be bigger concerns, such as issues around privacy and confidentiality (50%), friendliness of staff (47%), number of visits and time needed to participate (46%), the possibility of receiving a placebo (37%), and the potential of being paid to take part (16%). Most patients (93%) would offer to help researchers improve trials, such as by giving feedback on protocols, outcome measures, recruitment materials, and providing ongoing feedback during trial participation. Conclusion: Patient engagement in research has been increasing in recent years, enabled in part by digital technology and online patient communities. Patients have the opportunity not just to be subjects in trials but true partners in research. Some groups such as the I-SPY cancer trial and the OMERACT group for rheumatoid arthritis measurement have successfully harnessed the power of informed advocates to improve their processes, make trials more patient-centered, and ultimately achieve better outcomes. To scale the lessons learned from these pioneers, new tools are required to enable consistent patient input in ways that can lead to better decision-making. Patient powered research networks appear to be particularly enriched for patients who have either been in clinical trials or who have a high degree of interest in taking part in them. Therefore they may serve as a useful venue to explore ways to optimize trial design and operations by enabling researchers to listen to patients’ concerns in a way that is fast, repeatable, and with results that can generalize to a broader population easier than individual advocates or small focus groups. We identified trends for differences between demographic and disease subgroups that will be explored with a larger sample size to enable the construction of a “Trials Experiences Database” that can be queried across a range of conditions. Furthermore we intend to upgrade functionality to PatientsLikeMe that would allow patients to be made aware of trials for which they might be eligible, gain their feedback on the decision-making process they go through when deciding to enroll, and once enrolled receive ongoing feedback about their Poster Abstracts | diahome.org/DIA2014 21 DIA 2014 50TH Annual Meeting June 15-19 | San Diego, CA experiences of being a participant to help trial sponsors and researchers to optimize their clinical operations. T 45 Delivering Quality Systems Globally Craig Burnett Hospira Objective: A North Carolina Life Sciences Manufacturing Plant was looking for a way to innovate and improve their Quality Systems while reducing the total cost of ownership and risk. Implementation needed to include Mobile iPad access, dynamic form and streamlined dynamic workflow along with updated manufacturing execution document composition and data tools. Method: Project began in 2011 with implementation of Alfresco. Incremental additions to Alfresco’s open platform at a costeffective pace have included add-ons for dynamic form and workflow for change control along with iPad access. Latest efforts have included dynamic creation and electronic completion of manufacturing batch records. Results: Company was able to substantially streamline process and improve user experience at a cost-effective pace. Platform allows company to continue to innovate on user experience and leverage additional capabilities within a validated, compliant environment. Solution is expanding to additional manufacturing plants. Conclusion: As a world class life science manufacturing plant, the company was looking for innovative ways to implement new interfaces and improved processes for typical Quality System initiatives around Document control. Rather than selecting an older, legacy, proprietary platform and vendor, in 2011, the successful implementation of Alfresco has led to additional successes for an improved user experienced while insuring compliance with company quality standards. The incremental implementation approach was able to significantly reduce the overall risk of the project both in regards of timing and cost. T 46 Creating Standard Analyses and Displays for Common Safety Assessments in Clinical Study Reports Karolyn Kracht, MS AbbVie Inc. Objective: The objective of the project is to provide recommended analyses and displays (with associated code) for common safety assessments, with a focus on Phase 2-4 clinical study reports and integrated submission documents. Method: A cross-industry working group, primarily of statisticians from the pharmaceutical industry, has been formed and is creating several white papers outlining recommended analyses and displays. Results: The working group has finalized a white paper titled “Analyses and Displays Associated with Measures of Central Tendency – Focus on Vital Sign, Electrocardiogram, and Laboratory Analyte Measurements in Phase 2-4 Clinical Trials and Integrated Submission Documents” and a white paper titled “Analyses and Displays Associated with Non-Compartmental Pharmacokinetics – Focus on Clinical Trials”. The following four additional white papers are in progress: 1) Analyses and Displays Associated with Outliers or Shifts from Normal to Abnormal – Focus on Vital Sign, Electrocardiogram, and Laboratory Analyte Measurements in Phase 2-4 Clinical Trials and Integrated Submission Documents; 2) Analyses and Displays Associated with Adverse Events –Focus on Phase 2-4 Clinical Trials and Integrated Submission Documents; 3) Analyses and Displays Associated with Demographics, Medications, and Disposition – Focus on Phase 2-4 Clinical Trials and Integrated Submission Documents; and 4) Analyses and Displays Associated with Hepatotoxicity –Focus on Phase 2-4 Clinical Trials and Integrated Submission Documents. Review of these white papers is open to anyone interested in providing feedback. (See www.phusewiki.org). Some of the recommendations will be covered in the poster for specific feedback by DIA attendees. Building the Script Repository to support the recommended analyses and displays is also in progress and open to anyone interested in supporting the effort. Conclusion: Industry standards have evolved over time for data collection (CDASH), observed data (SDTM), and analysis datasets (ADaM). Although substantial progress has been made, additional standardization can improve product development. Development of standard tables and figures with associated analyses will lead to improved product life-cycle evaluation by ensuring reviewers receive the desired analyses for the evaluation of patient safety. More importantly, having an organized process for shared learning of improved methodologies can lead to earlier safety signal detection and better characterization of the safety profile of our products. Special acknowledgement to Mary Nilsson, project lead and co-author, and to members of the PhUSE Computational Science Symposium Standard Scripts for Analysis and Programming Working Group, White Papers Project Team who have contributed to the white papers, and to those who have provided review comments. W 01Evaluation of Operating Characteristics of MMRM Analysis Using All Available Longitudinal Data at Interim Compared to ANCOVA Weining Robieson, PhD AbbVie Inc. Objective: The objective of this simulation study is to understand the operating characteristics of ANCOVA and MMRM models using all available data at interim analysis. Four different longitudinal response scenarios, 3 dropout profiles and 3 enrollment rates are examined. Method: ANCOVA and MMRM were used to analyze simulated longitudinal data with and without including ongoing subjects at interim. Type 1 error rates were examined in null cases. Probability of claiming success and bias of point estimates were assessed in cases where there were treatment effects at endpoint. Results: At interim, MMRM analyses with or without data from ongoing subjects provided more robust results than ANCOVA analyses. MMRM models utilizing data from completed and ongoing subjects increased the information fraction for the analysis at interim compared to using completers’ data only. For both MMRM models, the information fraction at interim decreased with the increase of dropout rate, while the effect of enrollment rate on the information fraction appeared to be small. In scenarios that there is no treatment effect at the study endpoint, the probability of erroneously rejecting H0 at interim was similar for MMRM analyses without and with ongoing subjects. In scenarios that there is a treatment effect at the study endpoint, the probability of rejecting H0 at interim (claiming success) was higher for the MMRM model with ongoing subjects than without ongoing subjects. The biases of treatment effect estimate were similar between MMRM models with or without ongoing subjects. ANCOVA models had bigger bias of the point estimate compared to MMRM models, especially if all available data were used for interim analysis. Conclusion: Regardless of longitudinal treatment response scenarios, dropout rate and enrolment rate, MMRM model utilizing all available data at interim analysis consistently improves efficiency without increasing bias of point estimates for treatment effect. W 02 Recent Developments in Scaled Average Bioequivalence Pascal Guibord, MSc Algorithme Pharma Inc., Canada Objective: A review of the recent developments and its impact on the sample size, statistical analysis and interpretation of the study results will be presented. The impact of the type of implementation, the regulatory constraints, the study design, and the selection of subjects will be evaluated. Method: The 2 implementations of the scaling approach (FDA, EMA) will be described and compared. Data collected at Algorithme Pharma will then be used to illustrate the diffrences in the 2 implementations and to show the reduction in sample size resulting from it. Results: A total of 455 studies conducted at Algorithme Pharma evaluated under FDA or EMA regulation were reviewed. Studies included in this analysis were grouped in 3 types of design: 2x2 crossover (N=399), partial-replicate (N=19) and full-replicate (N=37). Poster Abstracts | diahome.org/DIA2014 22 DIA 2014 50TH Annual Meeting June 15-19 | San Diego, CA Reference-replicated designs (partial or fully replicated) represent two main benefits when compared to the standard 2-sequence 2-period crossover design (2x2). They allow the use of the scaling approach for the assessment of bioequivalence of highly variable drugs and, as the reference is replicated, they require less subjects to be exposed to the drug being tested in order to achieve bioequivalence. Results show that the sample size required to prove bioequivalence does not increase as much in reference-replicated designs than in a 2x2 crossover when the test-to-reference intrasubject coefficient of variation (ISCV) increases. Linear trend lines clearly showing the differences between the design types will be presented for Cmax and AUCT. The studies included in this analysis represent a wide range of ratio and testto-reference ISCV that are representative of the variety of studies that are conducted. Conclusion: The use of reference-replicated designs is a more effective design than the 2x2 design when the drug is sufficiently variable so that the sample size required becomes large. The use of the scaling approach proved to be also effective when the reference intra-subject variability is high (>30%). W 03An Overview of Both Current Best Available and Next Generation of Drug Therapies for the Treatment of Depression Annette Williams, MBA, RPh Quintiles Inc. Objective: Understand current state of play regarding antidepressant therapy. Appreciate role of side effects in patient non-compliance with anti-depressants. Have an overview of novel therapeutics in pre-clinical and clinical trial studies. Method: The methodology employed for this research included a literature search of PubMed with the key words ‘Novel targets for the treatment of depression’, compared with Up-ToDate monographs of marketed antidepressant medications and ADIS safety profile search of specific antidepressants Results: Ever since the development of the first drug therapy for the treatment of depression, prescribers, caregivers and companies have struggled with issues of patient non-compliance. These issues are due to a number of factors, including non-responsive treatment groups and the varied range of adverse drug reactions associated with antidepressant treatments. This paper aims to provide an insight into the current best available treatments for depression, focussing on: targets in the body, efficacy profiles, safety profiles and current problems and solutions for patient non-compliance. Furthermore, this review will examine possible future treatments for depression by looking at novel therapeutics in pre-clinical and clinical trial studies. Conclusion: It will attempt to determine whether novel targets of treatment or more specific targets of treatment could have an impact on the safety profiles of antidepressant medication without reducing its efficacy. Overall, we will assess whether the next generation of antidepressant treatments will demonstrate superior safety profiles in concurrence with efficacy profiles of similar or superior value leading to better compliance and overall improving the health of people suffering with depression worldwide. W 04 Health Literacy Assessment, Usability Testing, and Revision of a European Union Risk Management Plan Public Summary Karen Lockwood Eli Lilly and Company Objective: The authors assessed and performed consumer usability tests (UTs) on an original and revised version of a European Union Risk Management Plan (EU RMP) public summary with the goal of improving document understandability and usability using best practices in health communication and health literacy. Method: This 2013 study was conducted by Health Research for Action (University of California, Berkeley) and Eli Lilly and Company. Assessment was performed using the Suitability Assessment of Materials (SAM) tool. UTs were conducted with American adults who had low-toaverage education levels. Results: The original EU RMP public summary scored 10/34 points (unsuitable) on the SAM. The SAM testing showed that the text was written at a college level, the context and purpose of the document were unclear, the format and language were complex, and little information was focused on actions that consumers could take. Results from the first round of UTs were aligned with the SAM findings, highlighting common health literacy issues, including problems with the participants’ understanding of risk information, difficult concepts, statistics, words, and medical terms; reading dense text blocks; selecting key points from text blocks; understanding tables; and getting tired when struggling to understand information. Revisions to the EU RMP public summary were necessarily conservative, constrained by regulatory requirements for the document. Revisions that were made within the regulatory constraints did increase the document’s SAM to 20/34 points (adequate). The reading level was improved to a 9th-grade level, descriptive introductions to sections helped to clarify the context and purpose of the document, much technical language and jargon were eliminated or explained, and usability was improved somewhat by placing more emphasis on consumer actions where possible. Most of the revisions made after the first round of UTs were successful in improving its understanding and ease of use in the second round of UTs. However, despite improvements, participants still struggled to read and understand parts of the document. The focus on risks was concerning to participants, and some did not seem to understand that risk is an unavoidable issue for all medications. Other inherently difficult concepts included potential risks, unknowns, randomized controlled studies, and risk frequencies. Conclusion: The complexity of drug/device risk information is of global concern, often exceeding patients’ abilities to understand and effectively act on it. Some best practices in health communication and health literacy can be incorporated into EU RMP public summaries in order to improve document understandability and usability . Recommendations that are both effective and achievable without major policy changes regarding the document scope and structure include: adding introductory text to explain the purpose and focus of each section in lay language; referring consumers to other easily understood and more comprehensive information on the drug/device; using bullets to make the text/tables easier to read; using frequencies (e.g. 1 of 100 patients) rather than percentages to express data; using consistent formatting for tables; avoiding Roman numerals; and putting headings, subheadings, and table titles in lay language. However, the EU RMP public summary contains many inherently complex concepts, which can lead to misunderstandings. An important, but more difficult, improvement would be to clarify the context of the document, in order to provide consumers with more guidance on how to read and use it. Such a change would require policy decisions from stakeholders, including European regulators. If stakeholders would consider making major changes to the document, key recommendations would be to reassess the intended use of the document by consumers and to rethink its scope and structure, with close involvement of patients and caregivers. A further recommendation would be for stakeholders to develop a template with input from members of the intended audience(s), using usability testing in an iterative fashion to produce a document that is satisfactory to participants and that objectively shows their understanding of the content. W 05 Coordination of a Multi-site Cell and Gene Therapy Study in an Academic Medical Center: A Success Story Bambi Grilley, RAC Baylor College of Medicine Objective: This initiative was designed to provide an infrastructure to support the development, implementation and conduct of a multi-site cell and gene therapy protocol utilizing a product manufactured at an academic medical center under a Sponsor-Investigator Investigational New Drug application (IND). Method: A Memorandum of Understanding(MOU) was developed and signed that outlined regulatory and data management responsibilities of the Academic Medical Center(PI) and a Poster Abstracts | diahome.org/DIA2014 23 DIA 2014 50TH Annual Meeting June 15-19 | San Diego, CA CRO. The MOU was sent to the Food and Drug Administration(FDA) as part of the IND submission to codify the roles and responsibilities. Results: The study was submitted to the Office of Biosafety Activities, National Institutes of Health (NIH OBA) and the FDA by the Sponsor Investigator and was allowed to proceed. The study was ultimately submitted to and approved by IRBs and IBCs at eight academic medical centers within the United States. Conduct of the study was overseen by a fully constituted Data Safety Monitoring Board (DSMB). The study was successfully activated in 2008 and a total of fifty (50) patients were treated. The study was closed to new patient entry in 2012. Conclusion: The results of the study were adequate to support further use of the product under an Expanded Access Protocol. In fact, of the 50 patients with severe, refractory illness due to infection with EBV, CMV, adenovirus or a combination of those viruses, the cumulative rate of complete or partial response at six (6) weeks post-infusion was 74% (95% CI, 58.5% - 89.5%) for the entire group. Only four (4) responders had a recurrence or progression. The product proved to be a meaningful treatment alternative for these patients. This regulatory approach proved an efficient and effective way to expand the use of a cell and gene therapy product to more than one institution. W 06An Innovative Way of Providing Timely Responses to Questions Related to Ingredients/Allergens Irene Sheng, PharmD Bristol-Myers Squibb Company Objective: Approximately 85% of inquiries related pharmaceutical properties of a product are not addressed at the time of request at Bristol-Myers Squibb. The objective was to create and implement a customer-focused solution to provide timely responses to questions related to ingredients/allergens of products. Method: With the assembly of the appropriate team members cross-functionally (Global Medical Information, Global Regulatory and Legal colleagues), team developed a robust ‘realtime’ repository along with approved response templates and work instructions. Results: As a result of this project, a global ingredient database is now available that covers approximately 50 global brands. The company enhanced customer experience by reducing fulfillment time from an average of 2 weeks to real-time delivery of information on a specific ingredient for a product. Approximately 90% of ingredient-related product inquiries can now be addressed in real-time compared to the 15% that was identified previous to the development of the repository. Conclusion: This innovative and streamlined process meets the company’s business needs as well as supports the needs of their customers by allowing them to make informed decisions on their health at the time they need the information. The successes of this project support the exploration of gathering other pharmaceutical property-related information on the company’s medicines, and have built a lasting and strong partnership across the matrix. W 07Evaluating and Supporting the Increasing Patient Need for Delivery of Clinical Trial Supplies Direct to Their Homes Esther Sadler-Williams, MPharm, MSc, RPh Catalent Pharma Solutions, Inc., United Kingdom Objective: The increasing global nature of studies can result in long travel times to clinical sites for patients which can compromise compliance thus the objective was to explore options to support the site and improve patient compliance through delivering clinical trial supplies direct to patient homes. Method: An evaluation of documented patient experiences in the literature and of an UK NHS (National Health Service) organisation was undertaken. Together we were able to derive and implement regulatory compliant processes to deliver Clinical Materials to direct to patients. Results: Review of the available literature confirmed that the actual number of sites that participate in more than one clinical study is not increasing. To increase the likelihood that they remain in the study, patients themselves are requesting that clinical trial supplies are delivered direct to their homes where possible, as a minimum for re-supplies. Setting this requirement against the current cGMP/ cGCP regulations provides a challenge as this direct delivery of clinical supply medication to patient homes is not possible and nor does the capability exist in all countries worldwide. Working with an National Health Service provider in the UK, as well as sponsors, regulators and other third party providers, it was possible to identify various regulatory compliant possible distribution pathways for many key global regions, including the US where the situation is further complicated by individual state laws. This methodology increased the probability of patients complying with the clinical protocol and streamlined the (re)supply process. In more traditional models, transportation by the patient from the clinical site to the patient home may not utilize processes to prevent temperature excursions. This is apparent in more products that have cold-chain requirements after the point of dispensing, without supply of, for example cool bags for patient transport. Conclusion: With an increase in the number of worldwide studies and with more clinical protocols involving biologics coupled with the increased pressure to recruit and retain patients as well as optimize patient compliance, new and innovative ways need to be found to optimize the delivery of clinical supplies to patients. Review of the literature and regulatory data suggests that in certain countries opportunity exists to ship clinical materials direct to patient’s homes. Different distribution models can and are being derived and employed to support this which improves the overall patient experience, supports their work life balance, and increases the likelihood of patient retention and compliance with the drug regimen and clinical protocol. Additional Author: Dr Samantha Carmichael MRPharmS W 08New Business Acumen Tool Guides Strategic Thinking: Learn How to Increase Your Value to the Company and to the Industry Ilyssa Levins Center For Communication Compliance (CCC) Objective: Improve leadership agility and performance by learning how to: articulate your value to business partners; move from tactical to strategic thinking; share best practices to accelerate career advancement/contribute to business success; and utilize an HBA/DIA tool for career development. Method: Strategic acumen and innovative thinking are as important as technical expertise for product development/commercialization. When Regulatory, Legal, Medical and Development think like the business, solutions resonate with a company’s mission/goals. The Business Acumen Tool addresses this need. Results: It’s no longer enough to get a drug or device through the approval process. Product success is now based on reimbursement and how new influencers, like payers and patient groups, identify product value. Regulatory affairs, medical, legal and clinical development functions can support a company’s business plan and product differentiation if they understand how their business partners think. This includes honing business acumen and executive presence skills. The Business Acumen Tool focuses on five parameters designed to help these functions recognize, package and communicate their value to the business from development to commercialization. 1. Optimize the label to make the strongest, most critical claims. At least five years pre-launch, these functions create meaningful product differentiation from key competitors and the best way to design the research to secure that claim. They carefully consider product life cycle management, including ways to replenish the pipeline; help determine which data can deliver regulatory exclusivity and support the patent life of the product; and maximize regulator interactions to secure the targeted product profile. 2. Make the case for reimbursement. It’s critical to design studies that demonstrate to payers how innovative products are more valuable to patients than existing therapies based on data and labeling; how future competitive products could impact the reimbursement status of a product; which claim(s) would be most effective at earning, and keeping reimbursement status. 3. Ensure commercial advantage in the face of regulatory climate and health policy changes. Poster Abstracts | diahome.org/DIA2014 24 DIA 2014 50TH Annual Meeting June 15-19 | San Diego, CA Insights and expertise of medical and regulatory affairs can help companies plan and prepare for regulatory outcomes. 4. Develop effective and compliant selling materials. It’s key to focus on assessment of competitor labeling and shorten review cycle time for promotional materials. 5. Engender trust among external stakeholders. Without these, the business cannot grow. Conclusion: The pharmaceutical industry is facing new challenges that require bold thinking at this time of change. Leadership in Regulatory, Legal, Medical and Clinical Development play critical roles at a time when both compliance and commercial excellence need to be prioritized. That’s why honing skills like business acumen and executive presence are so important for these professionals. In this way, they manage risk and help drive the business, from R&D to registration, and through product promotion. Specifically, regulatory, legal, compliance and medical functions help their companies: 1. Exceed business objectives and financial targets with clinical studies that differentiate products, replenish pipelines and establish higher bars of entry for competitors. 2. Enjoy a competitive edge by paving the approval pathway for new indications in the shortest amount of time through new evidence generation strategies that deliver required data for payer reimbursement. 3. Expedite entry into key emerging markets through an intimate understanding of global registration guidelines, approval processes and more cost-effective ways to register products and protect patents Optimize competitive claims compliant with government regulations to make marketing campaigns more effective and durable. 4. Engender trust among key opinion leaders and global regulators through proactive and transparent communication about product effectiveness and safety enhancing corporate reputation which impacts purchase intent and brand loyalty. W 09 Complexity in Protocol Design: Does it Lead to Better Clinical Trial Outcomes? Rebecca Hummel CNS Healthcare Objective: Protocol complexity has increased over the last fifteen years; however, it is unclear whether this trend has led to better trial outcomes. This is a follow up to our 2013 poster, examining more data and increasing statistical power to explore the effect of protocol complexity on trial outcomes. Method: Data were collected from 73, phase 2 through 4, double-blind, placebo-controlled clinical trials from 2002 to 2011. The trials were assessed as successful or failed based on whether there was statistically significant separation of treatment from placebo on the primary efficacy measure. Results: A one-sided t-test was used to assess whether the 2 groups differed on 3 measures of study complexity: 1) the number of eligibility criteria, 2) the number of site visits in the trial, and 3) the total number of unique protocol procedures. In our sample, there was no difference between successful and failed trials on the 3 measures of trial complexity. Conclusion: Clinical trial outcomes may not be benefiting from more complex trial design. Datadriven, more efficient trial design may strike a better balance between containing clinical trial cost and achieving successful trial outcomes. Experienced research sites are in a unique position to work as partners with sponsors to optimize clinical trial design and improve trial outcomes. W 10 Corporate Integrity Agreement and Its Impact on Industry Abhishek Harde Cognizant Technology Solutions Corporation, India Objective: Understand the importance of Corporate Integrity Agreement (CIA) and its impact on pharmaceutical industry Method: The study includes an establishment of division to comply with various pharmaceutical regulatory acts, enabling through IT / Technologies. This includes but not limited to Sunshine Act, Safe Harbor Act, PhRMA and FDA enforced off label marketing regulations, Sarbans Oxley Act, etc. Results: Successful execution of CIA division within pharmaceutical company. Governments around the world have created laws and regulations governing our industry’s operations, including the research, development, manufacturing, marketing, promotion, and distribution of pharmaceutical products. These laws have a direct impact on daily work, and they govern our interactions with patients, healthcare professionals, researchers, customers, purchasers, governments, and others. Establishment of the division helped to make right, better and smart decisions, in compliance with CIA and pharma laws. Some of the aspects include: maintaining patient safety,protecting patient and customer privacy,conducting clinical research and trials, interacting with HCPs and other customers. Social Networking and media communication, laws governing international trade,Sunshine Act,etc. Covering all aspects within pharmaceutical company to ensure prevention of any type of lawsuit/ infringement/ violations of laws , best of the breed technology architecture is developed with 3.0 technologies. The technologies includes matrix collaborations ,artificial intelligence, Analytics and Big Data platform. This architecture is the backbone for executing the CIA laws and empowering the division within the company. Conclusion: Setting up a division for CIA and improving the effectiveness by implementing corporate regulations at federal and state level is the need of an hour.This gigantic task is next to impossible without enabling and applying world class technologies to the CIA division. The case study helps identifying the IT approaches for CIA enabled division to achieve 100% compliance from FDA and various regulatory agencies. W 11Giving Clinical Trial Start Up A Project Management Make-Over: Reducing Cycle Times Through Critical Path Focus Ben Quartley, PhD Covance Inc., United Kingdom Objective: Fast clinical trial start up is essential to finishing trial enrollment early, and this poster will demonstrate how it is possible to deliver faster start up timelines by treating start up as a project and applying project management methodology and processes. Method: Beginning in midyear 2011, project management methodology and processes have been applied to global study start up, resulting in a clear understanding of the critical path of the start up project, and the development of effective processes to reduce the critical path duration. Results: The poster will provide illustrative firsthand examples of the impact of successfully/ unsuccessfully optimizing the start up critical path, and the factors involved. It will also compare the firsthand examples to industry start up process capability data to show the quantitative advantage to be gained from optimizing the critical path. It will show that for two large international cardiovascular/ cardiovascular outcomes studies, successful optimization of the critical path produced start up timing in the 25 percentile of industry performance, whereas unsuccessful optimization produced start up timing in the 75 percentile. In absolute terms, the difference was remarkable: at the point where 80% of the sites were activated, there was an 8 month difference between the successfully and unsuccessfully optimized cases. Finally, the poster discusses how this approach can be used to educate internal and external stakeholders as to the impact of common critical path delays and ways to redesign processes to eliminate these delays. Conclusion: It has been shown in the research covered by this poster that well-coordinated teams can successfully streamline critical path activities during site selection (especially selecting sites for PSVs and making decisions post-PSV) and site activation (especially budget/ contract approval and pre-booking of SIVs), resulting in significantly shorter start up and enrollment cycle times. W 12 The Impact of Regulatory Reform in Mexico on Pharmaceutical Product Approval Rates Raul Vinueza Data-Pharma LLC Objective: The objective of this study is to describe the impact of the 2004 amendments to Poster Abstracts | diahome.org/DIA2014 25 DIA 2014 50TH Annual Meeting June 15-19 | San Diego, CA Article 376 of the General Health Law in Mexico on pharmaceutical product approval rates. Method: We compiled and analyzed product approval records from Mexico’s regulatory authority (COFEPRIS) for the years 2001-2013. Metrics of interest included product approvals per year, total number of manufacturers obtaining at least 1 approval, and central tendency values for approvals per firm. Results: The data shows a rapid decline in the rate of product approvals from 2005 onwards. From 650 products gaining approval in 2004, the approval rate decreased by over 70% in the following 6 years. The number of firms obtaining approvals exhibits a similar pattern, declining from 222 firms in 2004 to a low of 71 firms in 2010. Lastly, the data shows a consistent pattern across time for the number of registrations obtained by the typical firm. Over 75% of firms obtained less than 6 approvals each year, and about 50% of firms obtained less than 3 approvals each year. Conclusion: As Schmidt (2005) suggested, the amendments in 2004 were designed in part to address the problematic growth of the pseudo-generics market in Mexico that had resulted from a regulatory loophole that allowed manufacturers to market off-patent products without proving bioequivalence. Previously, product registrations were valid indefinitely, but with the new law in effect, firms are required to renew their registrations every 5 years. The costs and regulatory hurdles associated with renewing product registrations every 5 years under increasingly stricter requirements was predicted to have a deterring effect on sub-par manufacturers and pseudo-generic products planning to enter the market. The results provide evidence of a significant slowdown in the rate of firms and products entering the market. Since the product registration patterns for the typical manufacturer did not change significantly over time, the decrease in total approvals can be largely attributed to more firms either failing to meet requirements or opting to not register more products. Presumably, the subset of firms that are continuing to register products are the ones that have robust quality systems in place to continuously meet regulatory standards. Given the evident decrease in approvals, further studies are needed to ascertain how much of this trend is the direct result of low-quality generics being deterred from entering the market. W 13 So How DO You implement eSource: Practical Tips for Enhancing Efficiency, Data Visibility, and Site Interactions Ed Seguine, MBA Clinical Ink Objective: To provide practical tools for adopting electronic Source as your method for collecting clinical trial data. Method: It is critical to re-evaluate current processes that were developed based on using paper in clinical trials. We have conducted this evaluation and have developed specific processes designed to conduct completely paperless trials using electronic Source. Results: We will provide examples of specific process changes that are required to move from paper or EDC to electronic source/ These include changes in monitoring from administrative roles to analysis and intervention. We will also show how data management’s role also changes to provide more comprehensive reporting of all Risk Based Monitoring Domains. We will also provide examples of changes in workflow for start up and close out to shorten timelines. Conclusion: Technology can provide tremendous opportunities for enhancing trial efficiency but a careful assessment and modification of current processes is required to take full advantage of new technology. A change management model can assist in assuring that processes, training, and role descriptions are aligned to result in optimal technology utilization. W 14 Duloxetine Feeding Tube Study: Medical Information Example of Collaboration with Laboratory Scientists to Deliver Answers. Andrew Buchanan, RPh Eli Lilly and Company Objective: To demonstrate Global Medical Information (GMI) collaboration within GMI and with laboratory scientists to investigate and develop answers to frequently requested Health Care Practitioner (HCP) questions. Method: GMI identified a common HCP question of duloxetine administration through feeding tubes (>200 requests/year) with no optimal answer. GMI partnered with laboratory scientists to develop a protocol to mimic clinical practice and record observations of duloxetine delivery through feeding tubes. Results: Although participation in the design/ implementation of a study is not typical for GMI, a collaborative effort was helpful to design the study taking into account typical clinical practice. GMI wrote the study protocol, in accordance with published literature and consultations with experienced nurses and scientists, which was then accepted by the laboratory scientists. The primary study objective was to determine whether the intact pellets from a duloxetine 60 mg capsule, after being mixed in apple juice or water and injected into feeding tubes, would visually adhere to and/or physically obstruct nasogastric (NG) tubes (14 French silicone and polyurethane) or gastrostomy tubes (G-tubes) (20 French silicone). Apple juice (pH ~3.5) was chosen as a vehicle because previous data had demonstrated stability in this acidic liquid, and sterile water for irrigation was chosen because water is often used as a vehicle for administration of medications through feeding tubes in clinical practice. Study results showed that the majority of duloxetine pellets accumulated in the junction between the tip of the administration syringe and the entry point of the feeding tubes, and remained there even after flushing. Similar patterns were observed for each of 3 tube types, and with both apple juice and sterile water for irrigation. A summary of these study results was summarized in a medical letter, which is now provided to HCPs in response to unsolicited questions which continue to present on this topic. Conclusion: From the results of the laboratory study, we concluded that administration of duloxetine pellets through either NG tubes or G-tubes was shown not to be a dependable method for delivery of duloxetine. The accumulation of pellets in the tubes prevents accurate dosage of duloxetine to patients. These in vitro study data complement published literature on the administration of enteric-coated medicinal products through feeding tubes, much of which discourages this practice due in part to risk of tube obstruction. Overall, these results demonstrate the impact of cross-functional collaboration to propose and implement practical solutions in order to create meaningful responses for HCPs. In this particular example, by collaborating within GMI, we were able to capture an unmet customer need with potential significant patient impact. We were then able to assimilate expertise and partner crossfunctionally to research and deliver an answer, albeit with limitations, which is meaningful, readily available, and helpful to HCPs for making clinical decisions. The initiative describ ed here serves as an example of how important customer needs can be captured and resolved as a result of successful, non-traditional collaborations, which can ultimately and most importantly benefit patients. W 15 Targeting the Best Sites with an Analytical Site Selection Model Using Multiple Metrics Elizabeth Nielsen Quintiles Inc. Objective: We determine the best sites for a clinical trial by creating a data-driven score based on multiple site and investigator metrics and analytically ranking each site compared to other sites. Method: Through collaboration with multiple departments, we identify and gather metrics from each site to define and explain positive site characteristics and determine which metrics are the most helpful in quantitatively explaining the variations between sites. Results: The best sites are those which have the highest patient enrollment, the fastest cycle times and the fewest quality issues. Site metrics are grouped into three categories: patient enrollment, cycle time metrics, and protocol and GCP compliance. Each category is analyzed using Principal Components Analysis Poster Abstracts | diahome.org/DIA2014 26 DIA 2014 50TH Annual Meeting June 15-19 | San Diego, CA (PCA) to determine the optimal weighing of each metric. After the weights are determined, a linear combination of site metrics is created for each site and thereby establishing a specific score in each of the three categories for each site. Additionally, the three categories can be weighted to put more emphasis on one or more categories, perhaps at the request of the sponsor. Scores for one site can be directly compared to other site scores, where a higher score is more positive. The site scores can be ranked to delineate top, middle, and low tiers of ranked sites and filtered to determine the best sites within a country or region. Conclusion: We can use this site selection model to help determine the best sites for a specific study within each country. A site can be analytically chosen for a study based on known attributes. This allows for a data-driven approach to site selection established from multiple attributes of a site and principle investigator, thus enabling the CRO and sponsor to choose a site based on more than one aspect of site performance. The model quantifies these attributes and creates a score and ranking for each site. This score encompasses multiple attributes but condenses the information into one quantifiable number. The ensuing score is straight-forward and easily understandable, allowing for direct comparison of sites. The model results can be a strong guide for an experienced user who is familiar with local and regional differences. In this manner, optimal sites are selected for a specific study to insure a higher probability of successful study participation, faster and higher enrollment, and robust study completion. W 16 Central Recruitment Methodologies in a Global Clinical Research Study of a Pediatric Autism Spectrum Disorder (ASD) Program Allan Spera Forest Research Institute Objective: To review the recruitment strategies resulting in a rapid enrollment into a program of global investigational drug trials of the core symptoms of autism in children aged 6-12 years old with ASD, and to examine the characteristics of subjects identified through central patient recruitment. Method: Study-branded media and educational outreach strategies were used. Patients were referred to a study site after pre-qualifying via the study website or call center. Patient sources and their demographics were tracked and analyzed to enable an effective execution of the outreach. Results: From 2004-2013, the total number of both Untitled Letters and Untitled Letter Violations has exceeded the total number of Warning Letters and Warning Letter Violations. The average number of Violations/Warning Letter slightly exceeds the average number of Violations in Untitled Letters (2.9 vs. 2.5). In the first half of the assessment (2004-2008), the ratio Untitled/ Warning Letters issued was relatively equal; however, the Untitled/Warning Letter ratio has significantly increased by a ratio of 4:1 in the years 2009-2013. Conclusion: The Office of Prescription Drug Promotion is responsible for surveillance and enforcement of the Code of Federal Regulations in prescription drug promotion. Many factors determine whether OPDP issues a company in violation of these regulations an Untitled or Warning Letter. Indeed, we know OPDP utilizes a risk-based approach to help guide them on the issuance the violation letters. From 2004-2013, OPDP issued more than 250 different enforcement letters to industry. Our assessment found most enforcement letters issued to industry during this time period were Untitled Letters. Moreover, the ratio of Untitled/ Warning Letters has increased significantly in the last couple of years. This observance may be attributable to: increased industry awareness/ education, an increased understanding by industry of previous OPDP enforcement actions. Additionally, we also observed a slightly greater number of violations per Warning Letter vs. Untitled Letter which was relatively consistent over the studied period. W 17Evaluation of Shipping Systems to Maintain Sample Integrity in Clinical Research Mona Vimal, MSc Gilead Sciences, Inc Objective: Evaluate ambient and refrigerated shipping systems which effectively maintain biological integrity of human blood samples during overnight shipments. Method: Six shipping containers were evaluated. Human blood from 5 healthy donors was shipped within 24-48 hrs after draw in 5 separate shipments. The performance of each shipping container was evaluated by assessing the temperature and status of biomarkers using an ex vivo whole blood assay with ELISA Results: Three ambient (Therapak Category B Ambient; Thermosafe ambient; World Courier ambient) and three refrigerated systems (NanoCool™; Credo® by World courier; GTS-35 by Cold Chain) were evaluated. from -4°C to 34°C. The temperatures at high or low extreme end lasted 5 minutes to 6 hours in some containers. The results of the ELISA assay indicated that the extreme temperatures in the shipping containers had impact on the sensitivity of the biomarker measurements. Compared to the ambient systems, refrigerated systems, mainly the Credo® container, was able to maintain temperature from 2-8°C during shipping relatively consistently. The results of the ELISA assay from blood shipped within 24 hours showed that the sensitivity of blood to ex vivo stimulation was relatively well maintained in refrigerated containers compared to ambient containers. Conclusion: Clinical research samples play an integral role in drug discovery and development process. The stability and biological integrity of clinical samples has a significant impact on biomarker results. Therefore, the selection of an effective and suitable shipping method is critical. Based on the study conducted, we found that performance of the shipping containers did not always match the manufacturer’s validation specifications. Prior to selecting a shipment system for a clinical program, it is recommended that a series of well-designed mock shipments be conducted to validate the shipping system against the documented performance. In general, ambient shipping containers were not found to hold temperature during the 24-48 hour shipment. Among the refrigerated systems, temperature was consistently held per manufacturer specifications in two of the three shipping containers. Temperature excursions affected assay results, which concurred that sample integrity is crucial during shipment process. Depending on the scope of the clinical program, shipping method selected should also take into account the subsidiary factors like availability of the courier service, laboratory requirements, feasibility of scale up, cost, and site logistics, such as convenience and storage space at clinics. Authors: Hui Wang*, Anita Reddy*, Patti Butler**, Olga Acosta**, Mischa Hepner* and Mona Vimal* *Gilead Sciences, Inc., Foster city, CA **SeaView Research, Inc., Miami, FL Performance was evaluated by assessing temperature during shipping and status of biomarkers using an ex vivo whole blood stimulation assay with a commercially available ELISA. Study design accounted for variables like sample donor, shipment hold time, and ambient versus refrigerated shipping conditions. Performance of each shipping container was validated against temperature logs and assay results. W 18A Comparison of MedDRA SMQs Relative to Individual Preferred Terms for Signal Detection on a Large Insurance Claims Database Christopher Bone GlaxoSmithKline, United Kingdom Objective: The objective of this study is to compare the signal detection ability of Standardised MedDRA Queries (SMQ) against the individual Preferred Terms (PT’s) contained within the same SMQ in order to determine the potential value and dangers of using aggregate terms. The specified temperature range per manufacture’s specifications in ambient containers is 15-25°C and in refrigerated containers is 2-8°C. Our study results indicate that the temperature in ambient containers varied Method: A large US administrative health claims database (Commercial Claims and Medicare; 130 million records) was used to data mine four previously identified drug-event pairs. Relevant MedDRA SMQ’s were selected and the aggregate Poster Abstracts | diahome.org/DIA2014 27 DIA 2014 50TH Annual Meeting June 15-19 | San Diego, CA signal score (screening rate ratio) was compared against individual PT’s. Results: Four drug-event combinations for three drugs that received either a black-box warning or FDA alert were evaluated for signal scores (screening rate ratio, lower bound 95% confidence interval) using a commercially available observational data source. The preliminary results of the comparisons indicate that an aggregate signal score as provided by an SMQ generates a lower signal score than a relevant preferred term. The signal score for Varenicline and the preferred term ‘depression’ was 80% higher than the ‘depression and suicide/ self-injury’ SMQ. The signal score for Celecoxib and the preferred term ‘myocardial infarction’ was 84% higher than the signal score for the SMQ ‘myocardial infarction’. The signal score for Celecoxib and ‘gastrointestinal haemorrhage’ was 8% higher when using the preferred term than the ‘gastrointestinal’ SMQ. Telithromycin had a 25% higher signal score for the preferred term ‘liver disorder’ as compared with the SMQ ‘drug related hepatic disorders’. Conclusion: This research sought to determine the potential value of looking at aggregate terms (MedDRA SMQ’s) as compared to individual PT’s as well as identify potential dangers of using aggregate terms. The results from this study suggest that use of MedDRA SMQ’s in signal detection potentially risks suppressing a signal and delaying detection. MedDRA SMQ’s aim to improve characterisation of a disease or area of interest however their application in signal detection may be limited as the aggregate SMQ score is suppressed by other events in the SMQ when the actual PT term for the event is elevated. Due to the broad selection of PT’s in an SMQ it is also possible that an artificial increase in SMQ signal scores could occur if a less important term significantly influences the signal score relative to more relevant terms. Further research might consider examining the threshold for SMQ signal scores in light of the broad selection of terms and the objective of characterising a disease area over detection of a specific drug-event pair. W 19Introducing and Conducting Traditional Chinese Medicine Trials in the US: Challenges, Obstacles, and Potential Solutions John Li, MD, MBA ICON Clinical Research Objective: To review the status, trend of TCM related trials in Clinicaltrials. gov , their presence in different countries and regions, and therapeutic areas in US trials and identify common challenges and obstacles in introducing, designing, and conducting TCM trials in the US. Method: Used Traditional Chinese Medicine (TCM) as the search term to search clinicaltrials. gov on two separate dates; 25-Jan-2013 and 22Aug-2013. The status of trials arereviewed. Based on our experience and literature research, we identified challenges in designing and conducting TCM trials in the US. Results: As of 25-Jan-2013, searched clinicaltrials. gov with term of TCM, the authors identified 300 TCM related clinical trials; as of 22-Aug-2013, the authors identified 341 TCM trials, which include ongoing and completed trials. Among these trials, top ten countries/regions of having TCM trials are China, US, Taiwan, South Korea, Hong Kong, Germany, Singapore, Brazil, Italy, and Canada. The presence of TCM trials in country/ region are summarized Among the 300 trails on 25-Jan-2013 and 341 trials on 22-Aug-2013, China had 141, 168 trials, United States had 47, 47 trials, Taiwan had 27, 29 trials, South Korea had 22, 22 trials, Hong Kong had 15, 16 trials, Germany had 6, 6 trials, Singapore had 4, 5 trials, Brazil 4, 5trials, Canada had 2, 3 trials, and Italy had 2, 2 trials respectively. Among the 47 trials in the US, 16 (35%) trials are for oncology; 14 (29%) trials are for neurology/pain/psychiatry; 8 (17%) trials are for inflammation/infection; 5 (11%) trials are for internal medicine; and 4 (8%) trials are for others (allergy, obesity, and would healing). According to our experience of designing and conducting TCM trial in the US and literature reviews, we identified and summarized the common challenges/obstacles and appropriate approaches to overcome these challenges/ obstacles. Challenges/obstacles are, 1) Individual treatment as common practice for TCM therapy; 2) insufficient safety data for IRB approval; 3) Cultures difference and communication barriers; 4) Limited acceptance of TCMs for subjects in US. The potential solutions are 1) Standardize the prescriptions in TCM development; 2) Substantial mentoring the sponsor as early as possible for IRB approval process and requirement; 3) Identification and implementation of ideal staffing and increased the face to face meetings; and enhanced Technology for effective communication and information sharing; 4) Educate the target population through poster, newspapers, advertisement, etc. Conclusion: Collaborating with TCM companies based in China to conduct clinical trials in the US provides the unique opportunity for CRO to obtain the valuable experience of developing TCMs. Different practice for TCM therapy, sponsor’s insufficient safety data, culture difference and language barriers, and the subject’s limited acceptance are the main critical challenges for conducting TCM trials in the US. Be aware of these challenges and implementing appropriate approaches are imperative for the success of TCM trials in the US. W 20 Coherence of Observed-toExpected Disproportionality Methods Used for Pharmacovigilance at a Critical Threshold Geoffrey Gipson Janssen Pharmaceuticals, Inc. Objective: The purpose of this research was to demonstrate the insensitivity of signal detection to the observed-to-expected (OE) disproportionality method selected when the often applied critical value of 1.0 is used. Method: This work extends upon previous work (Gipson 2012) which demonstrated that many popular disproportionality methods can be calculated from a common equation. Monte Carlo methods for statistical distribution estimation were performed to demonstrate the logical consequences of the shared equation. Results: Much attention and discussion in the scientific literature has been focused on the relative merits of individual calculations belonging to a large class of methods often referred to as observed-to-expected disproportionality methods. Frequently debated topics in the Pharmacovigilance (PV) community include: confidence interval calculations; selection of signaling criteria and method performance; treatment of small observed case counts; and stratification. Here, we demonstrate a method of interpreting observed-to-expected disproportionality statistics which synthesizes findings across the various sub-methods. Specifically, we estimated the distributions of the disproportionality statistics through a Monte Carlo simulation where each of the variables in the 2x2 contingency table was modeled as a Poisson variable. The specific advantages of this method are: simple method for calculating confidence intervals; identical cumulative distributions at the often used critical value of 1.0; a natural handling of small case counts without additional applied shrinkage; straightforward extension of calculations for handling stratification. Conclusion: There are many different methods of calculating disproportionality available for identifying drug-event pairs in safety reporting databases. There are ongoing discussions in the PV community about what is the most appropriate method to measure disproportionality. This research demonstrates the insensitivity to method selection if a critical value of 1.0 is selected for the lower bound of the confidence interval. Effectively, this means that, if we define a signal as a significant deviation from and observed-to-expected ratio of 1.0, all OE methods give you the same result. This greatly simplifies the interpretation of the statistical results across the various methods and should provide PV practicioners with additional clarity when considering method selection. This work is an attempt to start building a framework for the simultaneous interpretation of multiple disproportionality statistics, instead of viewing the various methods as “in competition.” W 21Enhancing Project Management Tracking to Facilitate the Protocol Development Process Tracey Miller Leidos Biomedical, Frederick National Labs Objective: Develop a project management tracking tool for the National Institute of Allergy and Infectious Diseases (NIAID) Protocol Navigation/Protocol Development Program (PN/PDP) to evaluate milestones and manage project logistics throughout the research protocol Poster Abstracts | diahome.org/DIA2014 28 DIA 2014 50TH Annual Meeting June 15-19 | San Diego, CA development and approval phases. Method: Process steps, milestones, and key performance indicators were identified using the Six Sigma approach. These were integrated into a PN/PDP-specific workflow. Using the PN/PDP workflow, milestones and steps were aligned to create the PN/PDP-specific project management tracking module. Results: Logistics were initially tracked in spreadsheets. The growth of the PN/PDP protocol portfolio mandated a comprehensive, searchable PN/PDP-specific tracking module that supports the methodical documentation of activities. The resulting module reflects the PN/PDP’s efforts to efficiently and effectively manage the protocol development process. The module workflow has 9 milestones and 8 activities that a protocol may require as it is developed from concept to approval. The workflow is tailored to the projected services needed per protocol. The protocol progresses through the determined milestones as triggered by the completion of specified activities. The tracking module optimizes management of each protocol in development and enables the measurement of overall program performance. Specifically, it allows the PN/PDP team and management to: • Identify operational needs, required resources, and timelines at project initiation. Metrics can be extracted, allowing for visual displays of protocol status, staff assignments, and comprehensive, detailed project overviews. • Generate PN/PDP metric reports which display current and planned activities needed for each protocol and its current status in the workflow, staffing assignments, and other program metrics (e.g., NIAID scientific lab, protocol type). Reports can be generated by protocol as well as by overall PN/PDP protocol portfolio. The project manager can quickly identify the protocol status at any given time and the activities remaining for project completion. • Communicate with the NIAID intramural Regulatory Compliance and Human Subjects Protection Branch (RCHSPB) offices. Notifications are distributed automatically to applicable personnel when targeted milestones have been achieved that may require action within their departments. This streamlines the development process by keeping all applicable departmental requirements and deadlines transparent throughout the project. Conclusion: Preparing a compliant research protocol can be daunting for investigators. Regulatory review processes are often complex and multi-departmental, and are perceived as barriers by research staff. Furthermore, given the current uncertainty of research budgets, it is imperative that programs track milestones and key performance indicators to streamline processes and optimize program performance. The PN/PDP, in support of NIAID, identified the need for a project management tracking module to facilitate its mandate of delivering early interventions in protocol development, managing administrative and regulatory requirements, and providing writing support. Integrating the PN/PDP module into the database already in existence to track protocols under the sponsor’s purview and personalizing it for the PN/PDP represented a cost-savings approach. The module is a valuable project management tool that provides a dashboard of program metrics that can be used for program reports, planning, interdepartmental communication, decision-making, and publications. This research was supported [in part] by the National Institute of Allergy and Infectious Diseases. Funded by the NCI Contract No. HHSN261200800001E. W 22 Continued Tradition of Success: Critical Components of the Genzyme/Sanofi Oncology/MCPHS University Post PharmD Fellowship Christina Gallagher, PharmD MCPHS University Objective: To evaluate various components of the Genzyme/Sanofi Oncology/MCPHS University Post-PharmD Fellowship program and determine which factors are essential to ensure postfellowship success. Method: Electronic surveys were administered to all current Genzyme/Sanofi Oncology/MCPHS University Post-PharmD Fellowship program leaders (n=8) and fellowship alumni (n=16); participants were asked to identify factors that they felt translated into success post-fellowship. Results: Electronic survey results were collected from 88% (14/16) of fellowship alumni (graduates from 2005 – 2013) and 62% (5/8) of current program leaders. Of the fellowship alumni who completed the survey, 71% (n=10) received a job offer from Genzyme or Sanofi Oncology upon completion of their fellowship. Ninetythree percent (n=13) of alumni fellows surveyed agreed or strongly agreed that the type of work/ projects completed during their fellowship were critical to post-fellowship success and 43% (n=6) identified this as the single most important component. Other identified factors attributing to post-fellowship success included professional development training (n=12; 86%), networking (n=11; 79%), mentorship (n=11; 79%), and the program leader (n=10; 71%). Alumni reported that the least important component for success was the presence of PharmDs in their department (n=3; 21%). Alumni also noted in the comments section that experiences at scientific congresses, direct communication with thought leaders, and public speaking/presentation opportunities contributed to post-graduate success. Program leaders’ responses were similar: 60% (n=3) felt that the type of work/projects fellows completed was the most important indicator of post-fellowship success, followed by rotational structure and networking (n=1; 20% each). Forty percent (n=2) of program leaders felt that the presence of PharmDs within their department contributed least to post-fellowship success. Additionally, when asked for suggestions to improve the program, program leaders indicated that networking between co-fellows and greater involvement from the academic affiliate, MCPHS University, would provide more opportunities for collaboration and learning for fellows. Conclusion: The purpose of the Genzyme/ Sanofi Oncology/MCPHS University Post-PharmD fellowship program is to provide a comprehensive experience for Doctor of Pharmacy graduates within the biopharmaceutical industry. Survey responses were collected from fellowship graduates and program leaders of the clinical supplies/investigational products, global pharmacovigilance and epidemiology, global medical affairs, and regulatory affairs programs. Alumni and program leaders of the fellowship agree that the type of work/projects fellows complete, professional development training, networking opportunities and mentorship are critical program components and important factors for post-fellowship success. Although most program leaders hold a PharmD, alumni reported that the presence of PharmDs in their respective departments was of little importance to post-fellowship success. In an effort to provide a well-rounded fellowship program and maintain the tradition of success for post-fellowship graduates, program leaders will continue to strengthen the program by elevating the type of work/projects offered to fellows and providing additional networking opportunities and heightened mentorship W 23Assessment of Violations Cited by OPDP in Untitled and Warning Letters Issued from 2004-2013 Phil Reveal Meda Pharmaceuticals, Inc Objective: To assess the number of violations cited by OPDP in Untitled Letters and Warning Letters enforced from 2004-2013. Method: We assessed enforcement letters found on the FDA website from 2004-2013. From each Untitled and Warning Letter, the following was evaluated: number and types of enforcement letters from OPDP/year, number of violations cited in each enforcement letter, average number violations/letter per year. Results: From 2004-2013, the total number of both Untitled Letters and Untitled Letter Violations has exceeded the total number of Warning Letters and Warning Letter Violations. The average number of Violations/Warning Letter slightly exceeds the average number of Violations in Untitled Letters (2.9 vs. 2.5). In the first half of the assessment (2004-2008), the ratio Untitled/ Warning Letters issued was relatively equal; however, the Untitled/Warning Letter ratio has significantly increased by a ratio of 4:1 in the years 2009-2013. Conclusion: The Office of Prescription Drug Poster Abstracts | diahome.org/DIA2014 29 DIA 2014 50TH Annual Meeting June 15-19 | San Diego, CA Promotion is responsible for surveillance and enforcement of the Code of Federal Regulations in prescription drug promotion. Many factors determine whether OPDP issues a company in violation of these regulations an Untitled or Warning Letter. Indeed, we know OPDP utilizes a risk-based approach to help guide them on the issuance the violation letters. From 20042013, OPDP issued more than 250 different enforcement letters to industry. Our assessment found most enforcement letters issued to industry during this time period were Untitled Letters. Moreover, the ratio of Untitled/Warning Letters has increased significantly in the last couple of years. This observance may be attributable to: increased industry awareness/education, an increased understanding by industry of previous OPDP enforcement actions. Additionally, we also observed a slightly greater number of violations per Warning Letter vs. Untitled Letter which was relatively consistent over the studied period. W 24Accelerating Patient Recruitment Using In-Depth Market Research Insights: Collected via a 3rd Party From Clinical Trial Site Staff Jeff Jamer, MBA Merck & Co., Inc. Objective: This abstract demonstrates the power and efficiency of in-depth market research insights, implemented through partnering with a third party, from investigators (PIs) and study coordinators (SCs) to transform patient trial enrollment in a severely delayed study. Method: 2 phases of telephone interviews (TIs) were conducted with PIs and SCs to i.d. barriers to pt. recruitment and develop action plans to implement. Phase 1, i.d. barriers by conducting 45-min TIs with PIs and 90-min TIs with groups of 3 SCs. Phase 2 conducted similar TIs to evaluate possible actions. Results: The number of patients screened and randomized were collected weekly before, during and after the interviews were conducted and recommended actions implemented. Prior to the commissioning of the work outlined, patient recruitment for the clinical trial was projected to require 3 ½ more years. Following completion of the interviews and implementation of the recommended actions, patient recruitment for the clinical trial was projected to require only 1 ¼ years, a savings of more than 2 years. Patient screening and randomizing increased significantly, starting when the interviews began. When the recommended actions were implemented there was an incremental increase in the number of patients screened and randomized. There has been a 104% increase in trial enrollment since implementation of the market research compared to the previous enrollment trend line. No other activities occurred during this period that improved patient recruitment. The study resulted in four very specific recommended tactical tools desired by SCs and PIs, that have been implemented and have proven to have a significant impact. The apriori hypotheses (e.g. lack of patients) based on CRA feedback and site feedback directly to the sponsor were proven false. Additional survey results, administered to SCs and CRAs, were collected after implementation of the recommended tools. Results demonstrate that the large majority of both CRAs and Site Staff found each of the tools introduced based on the market research as either ‘very valuable’ or ‘somewhat valuable’. For the most preferred tool, 81% rated it as ‘very valuable’. Conclusion: PIs and SCs are often aware of specific factors impeding patient recruitment. However, they commonly communicate a limited amount of information directly to sponsors. Prior to the work outlined in this abstract, the clinical research sponsor contacted PIs and SCs directly to obtain input. However, these efforts did not result in any discernible increase in patient recruitment. The use of a third party to obtain inputs is necessary because PIs and SCs are reticent to communicate internal issues to sponsors; site staff must be mindful of the importance of sponsors for future trials. However, when interviews were conducted anonymously, PIs and SCs communicated the real barriers to patient recruitment. This initiative also highlights the opportunity to incorporate insights earlier in the clinical trial process. Insights can be leveraged in protocol design, recruitment strategy development, and educational and promotional communication testing. Additionally, this initiative highlights the importance of monitoring SC and PI feedback earlier in the execution of the trial, to uncover and diagnose issues prior to the trial experiencing a significant delay. There appeared to be a Hawthorne effect to conducting interviews anonymously with PIs and SCs. An increase in patient recruitment began shortly after the interviews were started and before any of the recommended actions were implemented. W 25Implementing a Standard Report Set for Risk Based Monitoring Domains Penelope Manasco, MD, MS MANA Consulting Objective: The objective of this abstract is to present an example of a Risk Based Monitoring Report Suite and how it can be used to assessed study quality. Method: We identified 11 domains that are needed in each trial for Risk Based Monitoring. Additional domains that are related to the primary efficacy endpoint are designed specifically for a trial or program. We developed a set of reports that provide data for each domain. Results: We provide examples of the reports that we use for each domain and examples of how these data are used to support risk based monitoring. We use the reports to guide weekly remote discussions with the sites and to develop and monitor user and site-based re-training or intervention. Conclusion: Risk Based Monitoring reports can be standardize for most domains. The results of the reports can then be used to guide the monitor’s site interactions and discussions with the PI and the Sponsor. Risk Based Monitoring reports do not have to be used to determine onsite visits exclusively, they can be a “report card” to help ensure higher quality study conduct. W 26Investigation of Association Between COPD Treatment and Cardiac Events With or Without Treatment for CoExisting Disease Ayako Takizawa, MS Nippon Boehringer Ingelheim Co., Ltd, Japan Objective: To assess the frequency of cardiac events reported in FAERS in patients who treated their background disease, COPD, and evaluate the effect of treatments for co-existing disease, Hypertension. Method: Reports of cardiac events submitted to US FDA’s adverse event reporting system (FAERS) from 2009-2012 were retrieved and analysed by reporting odds ratio (ROR) data mining algorithm. The ROR of cardiac events for used COPD medication were compared in class with/without anti-hypertensive treatments. Results: Adverse events were reported in 83586 patients treated with COPD medications during 2009Q4-2012Q3. In this period, 12888 cardiac events were reported in this population, corresponding to 3309 COPD medication-cardiac events pairs (anti-cholinergics; 632, betaagonists; 2032, inhaled corticosteroids [iCS]; 361, Methyl xanthines; 36, PDE4-inhibitors; 110). ROR and its 95% confidential interval (CI) values for anti-cholinergics, beta-agonists and iCS to other medications in FAERS were 0.27(0.250.29), 0.57(0.54-0.60) and 0.35(0.32-0.40), respectively. On the other hand, ROR for methyl xanthines and PDE4-inhibitors were 2.60(1.753.87) and 1.47(1.90-1.81). 28722 out of 83586 patients were treated with anti-hypertensive drugs. Hypertension is one of comorbidity of COPD. In patients treated with anti-hypertensive drugs, the risk of cardiac events increased, corresponding to ROR for hypertension treated population being 2.94 (2.83-3.05). ROR for inhaled medications had a similar trend in this population, whereas ROR and its 95% CIs for anti-cholinergics, beta-agonists and iCS to other medications were 0.45(0.40-0.52), 0.50( 0.450.55) and 0.38(0.30-0.48), respectively. ROR for methyl xanthines and PDE4-inhibitors were 1.37(0.52-3.61) and 1.02(0.72-1.44), respectively, including 1 in their 95% CIs. In this population, the lower limit of 95% CI of ROR for hypertension treatments except for ACE inhibitors, calcium blockers and beta1-selective adrenoceptor blockers was above 1 (ARBs; 1.23[1.00-1.52], ACE inhibitors; 1.03[ 0.81-1.30], renin inhibitors; 2.41[1.57-3.69], calcium channel blockers; 1.29[ 0.98-1.69], diuretic agents; 1.43[1.07-1.91], beta1-selecitive adrenoceptor blocking agents; 1.37[0.98-1.91], and alpha/beta-adrenergic blocking agents; 2.06[1.13-3.75]). Poster Abstracts | diahome.org/DIA2014 30 DIA 2014 50TH Annual Meeting June 15-19 | San Diego, CA Conclusion: Inhaled medications, which have COPD indications, such as anti-cholinergics, betaagonists and iCS, are not associated with cardiac events in FAERS, the spontaneous adverse event reporting system in the US. The trend of low risk of cardiac events shown in COPD treatment was similar in the population treated not only for COPD but also for hypertension. W 27 Reinventing the Study Build Process to Promote Consistency, Increase Build Efficiencies, and Reduce Overall Timelines Caroline Lin, MA Novella Clinical Objective: This purpose of this project is to reduce the amount of time devoted to developing the eCRF with the ultimate goal of reducing the development cost/time per eCRF by redesigning the study design process. Method: The traditional study build process is problematic because the iterative nature of the review and re-programming contributes to protracted eCRF approval timelines, often compromising later timelines or even delaying an EDC system Go Live. Results: In the redesigned process: 1. The DM creates the T&E prior to or just after the Data Collection Requirements meeting and provides it to the Study Designer. 2. The Study Designer programs the eCRFs in the target EDC system. 3. The Novella team reviews the eCRFs. 4. Draft eCRFs are sent to the client 48 to 72 hours prior to the OLSR. 5. The Client reviews the eCRFs in the target EDC system during the OLSR with the Study Designer and Novella team. 6. The Study Designer makes changes resulting from the OLSR (typically within a day or two). 7. The Client approves the eCRF after reviewing the documented changes requested. 8. The Study Designer documents the trial design. W 28 Collaborative Development of an Open Source Repository for Standardized Analysis Using Cloud Services Hanming Tu, MSc Accenture Objective: The objective of this poster is to describe the process, platform and progress of implementing an open source repository for the collaborative development of specialized programs to be used as analytical tools for clinical trial research, reporting, and analysis through cloud services. Method: PhUSE formed a standard script working group two years ago, consisting members from FDA and Industry. A script repository has been created for the collaborative development and a scriptathon event in March 2014 used to test out the cloud implementation. Results: Industry standards have evolved over time for data collection (CDASH), observed data (SDTM), and analysis datasets (ADaM). But for the industry and the regulatory authorities there are currently no standard tools available for the analysis of the standardized clinical data. The Pharmaceutical Users Software Exchange’s (PhUSE) Computational Science Symposium (CSS) formed a “Standard Script for Analysis and Programming” group for two purposes: 1) to create white papers outlining recommendations for safety analysis and reporting for clinical trial study reports and integrated safetyrelated submission documents, 2) to establish a platform for sharing and developing standard scripts collaboratively and for implementing the recommendations through cloud services. In the past two years, the group has accomplished the following tasks: Data was collected over twelve months (January 2013-December 2013). Over the course of the year, the time spent to create one form decreased from 10 hours to 3.63 hours. The duration of the eCRF spec development to OLSR and the duration of the eCRF spec development to client approval of the eCRFs decreased by 10 days each. The new redesigned process allowed us to average a savings of $11,000 per study build. Our savings for the year was $223,000. • Selected Google Code as standard script repository for development and storage of the PhUSE standard scripts o Some scripts exist in the repository o MIT license chosen o Process guidelines developed o Established the basic structure and process for managing the repository including o Folder structure and name conventions o Roles and responsibilities for each role o Tasks and duties o Process of tracking issues o Required metadata and recommended programming style for scripts o Test data and validation documentation • White papers describing recommended analyses, tables, figures, and listings o One white paper is complete o 5 others in progress Conclusion: Due to the cost and time benefits gained, Novella is proceeding forth with the new redesigned process for all study builds. Script-athon at PhUSE CSS 2014 is planned to test out the implementation of the open source repository with cloud services in R and SAS. The redesigned process will allow the Client to review the eCRFs at the OLSR in as little as one to two weeks after the Study Designer begins programming. The revised approach should remove the iterative process of review, reprogramming, and re-review that inevitably leads to prolonged eCRF approval timelines. How can we maintain the openness of the tools that we use and at the same time guarantees the security of the data? What we have done shows the possibility of leveraging the secure cloud systems in R and/or SAS to use the open platform to develop scripts and utilize the validated scripts to process shared and secured data sources. Conclusion: The goal of the standard script working group is to produce recommendations and establish a platform for the collaborative development of specialized programs to be used as analytical tools for clinical trial research, reporting, and analysis. This platform includes: • Identification of areas that can benefit from a standard set of analyses • Development of recommendations for analyses, tables and figures within a topic area • Creation of a process and guidelines for documentation and management of scripts • Incorporation of data standards whenever feasible From what we have experimented, we can conclude: • Google Code provides a scalable, reliable, and fast collaborative development environment for developing and sharing standard scripts and documents for data transformations and analyses. • It is mutually beneficial to both the industry and the regulatory authorities if an open source repository is available for storing and developing standard scripts • It is a good practice to use the white papers defining the cross-industry analysis and reports based on CDISC standards. • It is possible to implement the open source repository through cloud services, as it is tested in the Scriptathon event for utilizing the standard scripts from the repository in the secure cloud systems. Work together openly and collaboratively and we can achieve more than what we have hoped for! W 29 Quality of Japanese Clinical Trials and Proposed Strategy for the Trial Sites Toshiyoshi Tominaga, Osaka City University, Japan Objective: To find survival strategies for Japanese trial sites (institutions) in the current global drug development scene, with the underlying issues of greater role/responsibilities of trials sites in Japan, and the emerging risk-based definition of the clinical trial quality. Method: Existing reports on (a) the characters of Japanese clinical trials, (b) the current Japan’s policies on clinical development, and (c) the current risk-based approach to the quality of clinical trials were studied. The author formulated a strategy for Japanese trial sites based on the findings. Poster Abstracts | diahome.org/DIA2014 31 DIA 2014 50TH Annual Meeting June 15-19 | San Diego, CA Results: Characteristics of Japanese trials • The following are among the objectively observable traits of the Japanese clinical trials. (a) fewer subjects per trial site, with, however, difference between clinics and (large) hospitals (b) relatively high cost per subject (c) heavy dependence on monitors’ source data verification (SDV) for data accuracy approaches to design more efficient trials. What constitutes “Quality” ? • It has been found that the definition of “quality” has plural elements ( (a)fundamental merits ascribable to the populations, (b) compliance to GCP and protocol, and (c) data accuracy). The quality has been defined differently in the traditional understanding (100% in everything) and in the current risk-based approach (absence of errors that matter). Results: A working group consisting of multidisciplinary partners from academia, industry, patient groups, and government, including the FDA/CDER’s Antibacterial Drug Development Task Force was formed. The working group identified and focused on critical protocol elements where efficiencies leading to high quality, more feasible trials that can complete enrollment in a timely manner, could be introduced. Are Japanese clinical trials of high quality? • There have been separate reports regarding particular studies, in which such parameters as the number of queries, days before EDC inputs, responses to queries, number of findings in regulatory inspection showed the Japanese clinical trials’ quality being relatively high. However the author has not found a report showing a statistically significant difference in parameters across trials. The protocol elements of primary focus were: 1) patient population, 2) study design and endpoints, 3) safety considerations, and 4) operational issues. Discussion on risk-based approach • The discussion in Japan on the approach has apparently just begun. The author found that the discussion has been mainly on the sponsors’ conduct especially in monitoring and that there has not been much discussion on the expected role of institutions/investigators under the paradigm. Conclusion: This endeavor to improve protocol design and introduce operational efficiencies may help overcome obstacles for the conduct and regulatory review of HABP/VABP trials, hence addressing a critical unmet medical need. Conclusion: Based on the findings, the author proposes following strategies (or strengthening of the existing strategies); 1. National Level a) Further differentiation and cooperation among clinics and hospitals (advanced and others) b) Further encouragement in early phase trials 2. Hospitals with integrated clinical trial offices; a) Abandonment of 100% ism in every conduct and data b) Construction of in-house risk management system to supplement the sponsors’ risk-management W 30A Collaboration to Facilitate the Development of Antibacterial Agents for Unmet Need: Streamlining Clinical Trial Protocols Gary Noel, MD Janssen Research and Development Objective: This multidisciplinary effort aims to identify challenges in clinical trials conduct of antibacterial agents for the treatment of hospitalacquired or ventilator-associated bacterial pneumonia (HABP/VABP), and propose alternate Method: This collaboration includes the participation of a multi-disciplinary working group led by the Clinical Trial Transformation Initiative (CTTI). Several meetings and workshops were held to gain a wider understanding of issues, several solutions using a Quality by Design approach were proposed. Recommendations of the working group, including alternate approaches to design efficient and clinically meaningful trials to establish the safety and efficacy of new antibacterial agents for the treatment of HABP/VABP, will be presented. CTTI-HABP/VABP Protocol working group: Mark Behm, Sabrina Comic-Savic, Vance Fowler, David Friedland, Charles Knirsch, Martin Landray, Gary Noel, Christina Reith, Jonas Santiago, Brad Spellberg, Rosemary Tiernan W 31Global Regulatory Considerations for Biosimilar Approval Holly Groelle, PhD PPD Objective: To present a global perspective of biosimiar legislation, guidelines, and approvals in key markets. Method: A literature review and analysis of the current state of biosimilar legislation, guidance, and approvals. Published articles; competent authoritiy guidance and/or approvals; WHO and ICH Comparability Guidelines; and company websites. Results: Biologics have changed the practice of medicine delivering innovative solutions via antisense, cell, gene, monoclonal antibody, recombinant protein, and vaccine therapy. Patent expiry and high costs of reference biologics promote interest in biosimilars. In the past decade one-third of new medine approvals were biologics. Biologicals are expected to dominate small molecular entities as top sellers by 2018. Unlike new chemical entities and generics, biologics and biosimilars are not chemically identical and often are characterized by the manufacturing process. Developing a similar/ interchangeable to a reference biologic requires demonstration of comparability in quality, safety, and efficacy. Conclusion: The global landscape of biosimilar legislation, guidance, and approvals is presented in the context of the international standard: World Health Organization, European Medicines Agency, and U.S Food and Drug Administration. Explored is a comparison of the 12-year regulatory data exclusivity period afforded to the applicant first to establish its product as interchangeable with the brand-biologic pursuant to the U.S. Biologics Price Competition and Innovation Act (2009), 10-year new biologics (8-year data exclusivity and 2-year market exclusivity) and a 1-year extension for new indication in Europe, with legislation developing globally. W 32Impact of FDA Breakthrough Therapy Designation on the Regulatory Timelines of Chronic Lymphocytic Leukemia (CLL) Therapies Alex Wei Ernest Mario School of Pharmacy, Rutgers University Objective: The objective of the study is to determine the impact of the FDA’s new breakthrough therapy designation on the time to approval compared to the standard of care approved without breakthrough therapy designation. Method: The study utilized publicly accessible NIH clinical trial registry for trial information as well as the FDA and sponsor company press releases for regulatory milestones and pivotal trial data for the breakthrough therapies obinutuzumab and ibrutinib, as well as the standard-of-care, rituximab. Results: Obintuzumab is the first drug approved under breakthrough therapy designation. The phase I trial was initiated in 9/2007. Its pivotal phase III trial was initiated in 2010 and interim efficacy data was released in 1/2013. The sponsor submitted a regulatory application in 4/2013. One month later, breakthrough therapy was granted in 5/2013. The drug was approved in November, ahead of its PDUFA date of 12/2013. The pivotal phase III data had obintuzumab in combination with chlorambucil with an overall response rate (ORR) of 75.9%. Ibrutinib’s phase Ib/II trial was initiated in 2/2009. The phase III trial was launched in 10/2012 and it received its fast track designation shortly after in 11/2012. Breakthrough therapy designation was granted in 4/2013 based on phase II efficacy data. In 6/2013, the sponsor submitted a regulatory application and the FDA set a PDUFA date of 2/2014. In 12/2013, final adverse event and efficacy data for the phase Ib/II trial were released and 2 months later in 2/2014, it was approved for CLL Poster Abstracts | diahome.org/DIA2014 32 DIA 2014 50TH Annual Meeting June 15-19 | San Diego, CA based on phase Ib/II data. Patients in the phase Ib/ II study had an ORR of 58.3%. The IND application for rituximab was filed in 1992. Phase III trials in CLL began in 08/2004. Efficacy data from the Phase III CLL8 and REACH trials were presented in 12/2008. In CLL8, a regimen containing fludarabine, cyclophosphamide, and rituximab had a significantly higher ORR of 95% compared to a regimen containing only fludarabine and cyclophosphamide, which had an ORR of 88%. On 2/18/2010, rituximab was launched in the United States for both first-line and refractory CLL therapy. The total time from Phase I initiation to FDA approval was 6 years for obinutuzumab and only 5 years for ibrutinib. The time from regulatory filing to FDA approval was 7 months for obintuzumab and 8 months for ibrutinib. Comparatively, rituximab, the first biologic approved for CLL which now has a place in the standard of care, took 18 years from its IND to launch for CLL. Conclusion: Breakthrough therapy designation sets the precedent for a considerably accelerated drug development process. Recently, the increased focus on higher criteria for quality of care, along with advances in drug development technology, has necessitated the Breakthrough Therapy designation. Ibrutinib was approved solely on its robust phase Ib/II data and will have its approval confirmed by the phase III trial estimated for a 12/15 completion, leading to increased patient access for potentially life-saving drugs. Given CLL’s reputation as the second-most common type of leukemia in adults, the addition of two new agents, both approved within months of their Breakthrough Therapy designation, will allow physicians more options to treat their patients, enhancing patient care. Created in July 2012, The Breakthrough Therapy Designation remains a relatively new concept in the process of drug approval. The exact implications that the designation will have on the future of patient care are yet to be seen. However, the current data available suggests that breakthrough therapy designation can significantly expedite the process of drug development, allowing patients earlier access to drugs that considerably improve quality of life. W 33An Extension of Likelihood Ratio Test Based Method for Signal Detection in a Drug Class with Application to FDA’s AERS Database Yueqin Zhao, PhD FDA Objective: We extend the likelihood ratio test (LRT), recently developed for the detection of signals of adverse events (AEs) of a drug of interest in FDA Adverse Events Reporting System (FAERS), to detect signals of AEs for a class of drugs. Method: The performance of the proposed method is evaluated using power, sensitivity and false discovery rate through simulations. It is then applied to Gadolinium drug class in FAERS database. Results: In both simulated data sets and real Gadolinium drug data set, the extended LRT is shown to control type-I error and false discovery rate (FDR) while retaining good power and sensitivity for detecting signals. Conclusion: The extended LRT is shown, analytically and through a simulation study, to control type-I error and false discovery rate (FDR) while retaining good power and sensitivity for detecting signals. W 34 Maintaining Effective Pharmacovigilance Oversight: The Role of Remote Auditing Alun Tanner, PhD Remedion Consulting LLC Objective: Patient safety is a legislative and corporate priority; our objective was to understand the limitations, and quantify the benefits of conducting pharmacovigilance audits remotely in terms of maintaining effective oversight while using resources more effectively and reducing associated costs. Method: Five remote audits were conducted. Access to documentation was through webenabled document management systems, or by scanning and email. Interviews were conducted using remote-conferencing with screen-sharing technologies. The facility inspection was managed using digital photographs or video. Results: It is common practice to allow up to five days for the conduct of a routine pharmacovigilance system audit, including a nominal two days for travel to and from the site. When compared to this standard, it was determined that a routine audit of either a corporate affiliate or a vendor could be completed in three days using the remote auditing process without any reduction in either audit scope, or the quality of the oversight. Without the need to travel, there was a saving of ten days over the course of the five audits, which could have been used, for example, to conduct two or three further quality audits. Additional benefits included a significant reduction in travel related costs, and the ability to audit sites that were not readily available due to factors such as political unrest. During the pre-audit stage, management at the audit site were made aware of the differences between a virtual and an actual site visit, and any concerns raised were addressed. Using the remote process, a greater number of documents were requested in advance than would normally occur so that the auditor could better understand site processes and prepare a comprehensive list of questions prior to conducting the interviews. Secure access to documentation, either through a web-based validated document management system or through scanning, faxes or email, was an essential component of this process; comprehensive IT support, including adequate bandwidth, was therefore crucial. Interviews were conducted using tele- or video-conferencing; answers were verified using screen-sharing technologies allowing interviewees to effectively demonstrate steps in the process. Conclusion: Conducting pharmacovigilance system audits remotely, using the process developed during this pilot program, has proved to be is a cost effective way of maintaining oversight of on-site pharmacovigilance activities irrespective of whether these are conducted by a company affiliate or a vendor. These five audits included both routine case processing and the follow-up of remedial action plans. The remote process also lends itself to other relevant pharmacovigilance activities including regulatory inspection preparedness. A key benefit was the ability to maintain oversight of sites that might not be readily accessible to a normal on-site visit due to factors such as political unrest. Since this process allows auditing resources to be deployed more effectively, the number of audits conducted can be increased without the need for additional auditors or an increase in the travel budget. Although feedback from those participating in the remote audits was positive, it should be noted that this process does not replace the need for on-site audits but rather it allows a more sustained degree of oversight when integrated into a carefully planned, risk-based pharmacovigilance system audit program. W 35 Data Empowered Decision Making in a Pharmaceutical Company: Project Libraries and Workflows - Real Life Experience Mikhail Samsonov R-Pharm, Russian Federation Objective: This poster will justify the demand for, explain the capability and summarise results achieved from implementation of an innovative enterprise web-based platform designed to define projects and run business processes across a pharmaceutical business. Method: In August 2012 R-Pharm conducted business process review and mapping and started implementation of an enterprise wide platform to support activities across all key functions: regulatory, pharmacovigilance and product development. This was achieved by implementing two key technological solutions. Results: Gathering management data across a complex business such as a pharmaceutical company is a problem which has long been recognised. Pharmaceutical companies are increasingly faced with the complex task of becoming leaner and more efficient. This is down to both strategic and operational decisions – “doing the right things vs doing things right”. A system of interconnected project libraries was introduced in order to formalise project records and enable analysis across the pipeline of the Poster Abstracts | diahome.org/DIA2014 33 DIA 2014 50TH Annual Meeting June 15-19 | San Diego, CA projects. The structure adopted was Molecule, Drug, Non-clinical and Clinical projects. The project records in these sub-libraries were linked to each other, enabling to identify and analyse interconnections between them. In order to guide the activities on the projects, automated workflow tool was introduced. The system checks the entered data against predefined criteria. Once a task is completed, the workflow engages the next person in the process, moving the task from the Inbox of the current executor to the next person in the process. Implementation of the project library set up the foundation for universal project management activities across the projects. By capturing key metrics, such as priority index, incentives available from the government, contracting information, etc, a mechanism was put in place for quick prioritisation of activities in response to external or internal demands ( such as, for example, market changes and resource shortages). Implementation of the workflow platform allowed accelerating problem identification from months to days by providing real time data describing the processes. The reporting has a built in tools for identifying bottlenecks, by tracking duration of tasks, number of outstanding tasks and each user performance. A total of 15 processes have been implemented within the platform to date, ranging from Serious Adverse Event reporting to preparation of a Clinical Development plan and Due Diligence on in-licensing candidates. Conclusion: The use of a single enterprise platform brings a number of benefits, one of the most important of which is the ability to generate data to support decision making. The structure presented allowed to streamline project prioritisation by capturing project information in a fluid interconnected system of libraries and allowing to analyse the connections between projects as well as their key metrics. Implementation of workflow management produced real time data on the project activities, creating a data stream in support of optimising project related processes. As a result, R-Pharm obtained a complete management information dashboard, providing all the necessary information tools to optimise its portfolio and efficiency/effectiveness of its processes. W 36 Sample Size Re-Estimation Can Be Very Inefficient David Bristol, PhD Statistical Consulting Services, Inc. Objective: The objective is to present the inefficiencies associated with sample size re-estimation and to inform the users of such characteristics. Method: Simulations were performed for various scenarios for the true known parameters and assumed parameters used for initial sample size determination, resulting in either an underestimate, an overestimates, or the correct sample size. Results: Sample size re-estimation is typically inefficient and may be a major waste of resources, with too few or too many patients enrolled. This conclusion does not depend on whether the assumed parameters result in either an underestimate, an overestimates, or the correct sample size. Conclusion: The sample size for a clinical trial is typically chosen to control the power of the test corresponding to the primary efficacy comparison of two treatments, using assumed values of the true parameters, based on historical, clinical, and financial considerations. These assumed values may not be equal to the true values and thus the sample size may be inappropriate. An interim analysis can be used to check the appropriateness of the assumed values and the required sample size can be re-estimated using estimates from the interim analysis. Such procedures have become very popular in recent years and are often viewed as a way to conserve resources; however, there are inefficiencies that are rarely mentioned. The results of several simulations are presented to show that the re-estimated sample size may be much larger or smaller than necessary. Resources may be wasted because of these inefficiencies, which may be extreme. It is important that users are informed that such outcomes can occur. W 37 So You Hired a CRO…Now What? Advancing Clinical Research by Leveraging Government Sponsor Relationships with CROs Jessica Kloda, PhD Technical Resources International, Inc. Objective: To share how a U.S. Government Agency, serving as a sponsor for a large global portfolio of HIV/AIDS clinical trials, has successfully leveraged its relationship with a CRO to optimize regulatory support for the sponsor and its collaborators, in successfully conducting complex clinical trials. Method: Accountability and clearly defined processes are vital to this Government-CRO relationship, with quality metrics assessed regularly. Clear communication of expectations and continued outreach to stakeholders was essential in building the trust that ensures a successful clinical research structure. Results: Engaging in quality planning and using accountability metrics to assess performance has been instrumental in the success of this Government-CRO relationship. In addition, applying project management principles by designating leads for tasks has ensured consistent strong communication and that high quality work products are delivered on schedule. To build efficiencies, technology has been leveraged in data management and via electronic communication tools. The Division of AIDS Regulatory Support Center (DAIDS RSC), which is run by the CRO, has been integral in optimizing the use of the customized role-based Clinical Trial Management System (CTMS) called the DAIDS Enterprise System (DAIDS-ES), as the database of record for DAIDS collaborators. Utilizing a single CTMS across multiple collaborators requires careful coordination and also ensures consistency and accuracy in data reporting. Electronic communications are used across all DAIDS RSC tasks. Notably, e-Learning modules were developed to optimize the launch of new government policy manuals on safety reporting and essential document submissions, which are key in facilitating clinical trial site protocol operations. Similar strategies were used to deliver training to remote international locations in planning for audits and helped to ensure a cost-effective approach to promote compliance with regulations throughout protocol lifecycles. The trust established in this Government-CRO relationship has allowed the DAIDS RSC to pursue equally important collaborator coordination via face-to-face outreach. The DAIDS RSC holds Information Booths and supports consultative sessions at collaborator meetings in addition to providing presentations and conducting meetings with clinical trial Network Operations Centers. These efforts have helped to proactively identify gaps in awareness about available clinical research resources and in process inefficiencies that the Government was able to address. Conclusion: The experience with the DAIDS RSC shows that the Government can effectively leverage its CRO relationships to support critical research in advancing the fight against HIV/ AIDS. Effective sponsor oversight and improved efficiencies through this partnership have helped to enhance clinical research operations among DAIDS, the DAIDS RSC and other collaborators. As part of outreach to external collaborators, a “DROP-IN” program was instituted for sites whereby DAIDS and DAIDS RSC personnel meet clinical trial site staff on location to assess needs, discuss processes, and share resources and tools that may facilitate appropriate implementation of procedures and promote regulatory efficiencies and compliance. Such resources and tools developed included tutorials, checklists, and how-to videos that have been made available via the public and mobile-accessible DAIDS RSC website. The CRO has been an integral part of the Government’s efforts to maximize the use of new technologies and implement more efficient processes to advance the HIV/AIDS clinical research being performed by hundreds of DAIDS collaborators around the world, including clinical trial sites in resource-limited settings and diverse regions. The strong Government CRO relationship has significantly contributed to scientific achievements including studies that supported the 2013 FDA approval of Merck’s Isentress® in liquid form for use in pediatric HIV/ AIDS patients, the 2012 FDA approval of Gilead’s Truvada® - the first antiretroviral to be approved as prevention therapy for HIV, and the successful clinical trial, HPTN 052, which examined the use of antiretrovirals in serodiscordant couples to prevent HIV transmission and was recognized as Science’s “Breakthrough Study of the Year” in 2011. Poster Abstracts | diahome.org/DIA2014 34 DIA 2014 50TH Annual Meeting June 15-19 | San Diego, CA W 38Office of Prescription Drug Promotion (OPDP) Enforcement Overview From 1997 to 2013 Cyril Carrere, MSc Thomson Reuters (Scientific) LTD, France Objective: Assess the impact of FDA regulation on warning and untitled letters from OPDP (formerly Division of Drug Marketing, Advertising and Communications) and identify the most frequent deviations from the Code of Federal Regulations (CFR) for warning letters. Method: Warning and untitled letters sent (1997-2013) were analyzed. For warning letters, deviations from 21 CFR were identified and placed into 4 categories—Prescription Drug Advertising, Labeling, New Drug Promotion, and Investigational Drug Promotion—and within each, the numbers of citations were ranked. Results: From 1997 to 2013, the Office of Prescription Drug Promotion (OPDP) issued 771 untitled letters and 130 warning letters. On August 12, 1997, the FDA announced the availability of the Draft Guidance for Industry: Consumer-Directed Broadcast Advertisements (Federal Register: Volume 62, Number 155, [Docket No. 97D-0302]); this document had a major impact on the number of letters (warning and untitled) issued, at a time when companies increased the number of promotional campaigns on their products. Specifically, the large number of letters issued to companies in 1997 (139) and 1998 (156) was related to that upswing in promotional activity. A steady decrease in letters sent was observed from 1999 (121), the year in which the Draft Guidance was finalized, to 2002 (27). Numbers then stabilized, with a mean of 23.7 letters published per year until 2008. The increase observed in 2009 (39) and 2010 (51) suggests an FDA enforcement focus on Internetrelated promotional media. The analysis of OPDP warning letters confirmed a strong focus on Prescription Drug Advertising, representing 70.7% of all citations identified, followed by Labeling (18.9%), New Drug Promotion (9.9%), and Investigational Drug Promotion (0.6%). Within Prescription Drug Advertising, unsubstantiated claims (clinical, non-clinical) accounted for 53.4% of citations identified, followed by deviations linked to misleading with respect to side effects, contraindications, or effectiveness (19.5%), and to an omission of information related to side effects, contraindications, or effectiveness (15.3%). For Labeling, failure to provide adequate directions for use accounted for the wide majority (82.5%) of the citations identified. New Drug Promotion citations were related to a failure to submit under Form FDA-2253, while the promotion of unapproved uses was only observed in two letters. Conclusion: The OPDP enforcement activity varied depending on historical FDA guidance publications, internal reorganizations, and companies’ evolution in their promotional activity. This had an impact on the number of letters sent per year, with a peak of activity observed in 1997 and 1998, then again in 2009 and 2010. The analysis of the OPDP warning letters showed that the vast majority of deviations from 21 CFR belonged to the Prescription Drug Advertising category, in which unsubstantiated claims were predominant. Labeling deviations essentially highlighted failures to provide adequate directions for use, and the New Drug Promotion and Investigational Drug Promotion categories represented only a minor amount of deviations. W 39Enrollment of Pregnant Women in Medication Safety Research: MotherToBaby Pregnancy Studies Jennifer Zellner, PhD University of California San Diego Objective: The objective of this study is to examine enrollment in MotherToBaby (MTB) Pregnancy Studies, a group of U.S. and Canadawide pregnancy registries designed to examine medication and vaccine safety during pregnancy across a variety of maternal health conditions. Method: MTB studies conducted from 20002014 have focused on influenza and meningitis vaccines, antiviral medications, and medications for asthma or autoimmune diseases. Women are followed in pregnancy and at least 1 year postpartum. Data are collected from interviews, medical records, and infant exams. Results: MTB participants are recruited through physicians, direct to consumer marketing, and Teratogen Information Services throughout North America. Between 2000 and 2014, a total of 3,886 pregnant women enrolled in MTB pregnancy studies. Outcomes for exposed women are compared with a disease-matched group of women without medication exposure during their pregnancy and/or a control group of healthy pregnant women recruited using the same sources and followed using the same methods. Vaccine Studies enrolled 1,744 exposed women and 483 non-exposed controls; Asthma Medication Studies enrolled 247 exposed women and 244 healthy controls; and Autoimmune Disease Medication Studies enrolled 740 exposed women who met strict study eligibility criteria, 435 exposed women who did not meet eligibility criteria but whose pregnancies were followed, 487 disease-matched controls, and 420 healthy controls. Overall, retention in MTB studies has been high (lost-to-follow-up rate across studies is 2%), supporting internal validity of study results. Conclusion: One in six women in the U.S. receives a prescription drug for which there is limited or no information on human teratogenicity (Schwartz et al. 2005, 2007). Medication use during pregnancy continues to increase; in addition, some vaccines (e.g., influenza) are specifically targeted to pregnant women. Yet the lack of clinical trials involving pregnant women for most medications and vaccines means we have a very limited understanding of the effects of these exposures on the long-term health of babies and mothers. Pregnancy registries are one method for collecting this information, but have often struggled with recruitment of exposed pregnancies, high lost to follow-up rates, and lack of appropriate internal or external comparators. MTB studies demonstrate the capacity to successfully identify medication and vaccine-specific exposed pregnancies across a wide variety of therapeutic areas and indications, to recruit and retain women representing a broad geographic area, to enroll appropriate comparator pregnancies, and to conduct long-term followup of mothers and infants. Such information will help women and health care professionals better understand the effects these exposures have on infant health and development, which will in turn inform improved healthcare decision-making. W 40A Model for Centralized Monitoring: Reducing Costs While Ensuring Compliance, Risk Mitigation and Quality Badhri Srinivasan, PhD, MS Quintiles Inc. Objective: The poster will examine the potential benefits of Centralized Data and Operational Surveillance (CDOS), a novel approach to Centralized Monitoring. Method: The poster will describe how the CDOS model delivers value in four key areas: ability to impact clinical monitoring costs; decreased time to analysis-ready data; increased quality/reduced risk; and ability to impact medical monitoring. Results: CDOS can reduce clinical monitoring costs by as much as 20% through targeted monitoring, while ensuring site compliance, risk mitigation, and quality. Conclusion: CDOS fits well within the RiskBased Monitoring (RBM) model, which starts with an in-depth assessment of the scientific and operational risk of each protocol, followed by dynamic monitoring (on-site, remote or centralized) and focuses on those sites, data, patients and events that require increased attention. Data surveillance allows monitoring to be optimized and adapted as necessary throughout the trial, with ongoing reassessment of risk and appropriately timed responses. W 41 Customer Satisfaction and Communication Methods Used in Conducting Large Multi-Center Clinical Trials Barbara Del Curto VA Cooperative Studies Program Objective: The objective of this work is to develop processes that effectively identify customers, manage expectations and measure customer satisfaction results in a complex pharmaceutical project management environment of large multicenter clinical trials. Method: For this work we assessed and integrated Baldrige criteria, a project management maturity model assessments and Poster Abstracts | diahome.org/DIA2014 35 DIA 2014 50TH Annual Meeting June 15-19 | San Diego, CA customer engagement measurement techniques to clearly define customer’s requirements throughout the clinical trial life cycle. Results: In 2009 the VA Cooperative Studies Program Clinical Research Pharmacy Coordinating Center (PCC) received the Malcolm Baldrige Presidential Award which has a focus on customer satisfaction. The result of our work demonstrated that having a consistent and standardized communication approach that captures customer requirements has a direct correlation to customer satisfaction. The PCC has participated in design and management of multicenter clinical trials since 1976 and as the number of trials increased standardized, communications tool providing overall clinical trial information and design requirements was developed. The tool has evolved from being used only for budget development into a comprehensive approach used to manage customer and sponsor expectations in all phases of a clinical trial and improved communications across our internal cross-functional teams. Through the integration of performance excellence criteria and understanding our organizational project management maturity, we identified and developed the communication tool needed to maintain and improve customer satisfaction. Conclusion: Capturing and communicating customer requirements is key to ensuring that clinical trial design criteria are met. The following assessments were instrumental in validating the importance that is placed in meeting our customers’ expectations: (1) External validation from the Malcolm Baldrige audit team confirmed that our pharmaceutical project management processes fosters a culture that strives for customer satisfaction. (2) Conducting the PMI’s Organizational Project Management Maturity Model assessments validated that the PCC follows and utilizes standard practices and tools that are key to leading and managing clinical trial activities. W 42Easy as A,B,C? Adapting Pediatric Protocol Designs from Existing Adult Data and Study Templates Rona Grunspan Premier Research Group Ltd. Objective: Learn the main differences between pediatric and adult study design that must be addressed. Outline the medical considerations that every pediatric protocol should include. Breakdown protocol elements specific for children and family participation that will permit a study to succeed. Method: Scientific methods used for protocol design and observed in the authorship of clinical study proposals may be similar across scientific disciplines in human health research in which patient safety and GCP are central goals. This presentation will breakdown the key child-centric considerations. Results: Case studies to be attached to poster. Conclusion: Concepts in pediatric research design are unique and require special consideration by those first venturing into the realm of conducting clinical research with children as subjects or facing their first pediatric protocol deliverable. W 43 The Construction and Promotion of Medication-Used Safety Education for Traditional Chinese Medicine in Taiwan Tsung-Ta Wu Department of Chinese Medicine and Pharmacy, Taiwan Objective: The objective of this study is to intensify the correct knowledge of medicationused safety for traditional Chinese medicine in Taiwan Method: For this study, ten resource centers of medication-used safety for traditional Chinese medicine were established in Taiwan. We invited experts in various fields to develop five core abilities, SLOWS (See, Listen, Obey, Withdraw, and Select), for using medicine correctly Results: In this study, we held various promotion activities of medication-used safety education for traditional Chinese medicine (TCM), and the questionnaires were collected after medicationused safety educating. There are totally 1,284 questionnaires, and among them, there were 1,066 valid questionnaires. The result shows that the incorrect cognition can be significantly improved after educating. For example, the resources of purchasing TCM have been dramatically changed, and nearly 70% of people will choose Chinese medicine clinic and Chinese herbal pharmacy to buy Chinese herbal medicine rather than looking for unidentified resources. Furthermore, we also founded five classes of digital learning course of TCM and put them in website of National Academy of Civil Service for reference last year. According to the data from website, about 131,000 participants attended to the learning classes until December 31, 2013. Conclusion: The result from the questionnaires reveals that the promotion of medication-used safety education is successful to enhance the correct cognition. We also believe that the medication-used safety education is helpful to clarify a part of people with myth and misunderstanding of TCM. Therefore, we still should make efforts to improve the level of medical knowledge of TCM in Taiwan. W 44 Patterns of Regulatory Approval for Targeted and Immunotherapeutic Compounds Indicated for the Treatment of Metastatic Melanoma in the US and EU Jonathan Nguyen Diep Rutgers, The State University of New Jersey Objective: This study aims to track key primary and secondary endpoints used to support the filing of all approved compounds for the treatment of metastatic melanoma. Analysis of study endpoints will provide further understanding for the regulatory requirements of targeted and immunotherapeutic compounds. Method: We identified the primary and secondary endpoints of pivotal trials for approved mono- and dual-therapeutic compounds for the treatment of metastatic melanoma in the US and EU. All data was collected via publicly available regulatory resources such as clinicaltrials.gov and ema.europa.edu. Results: The preliminary results demonstrate that the key primary and secondary endpoints include overall response rate (ORR), duration of response (DOR), relapse-free survival (RFS), progressionfree survival (PFS), and overall survival (OS). Despite the unfavorable adverse effect profile and dosing regimen, earlier compounds such as dacarbazine were not required to meet the robust endpoint of overall survival (OS) in order to gain approval. However, as the standards for evaluation have evolved, tumor response rates (e.g. ORR) continue to be key endpoints, while more robust endpoints such as overall survival have emerged as important measures of efficacy. As new immunotherapeutic modalities move into the melanoma treatment landscape, regulatory agencies will continue to require companies to demonstrate increasing clinical and economic benefit. Conclusion: It is evident that over the years that the FDA and EMA agencies have adjusted preferred endpoints for the advanced or metastatic melanoma indication. These changes have become necessary as the standards in measuring patient outcomes continue to evolve. As a relatively new mode of treatment, there is an incomplete understanding of many immunotherapy compounds. As a result, the various required and recommended endpoints evaluated are utilized to identify further safety and efficacy benefits, about a treatment modality that is not thoroughly understood. To be noted the study analysis primarily evaluated FDA approval with minor evaluation of EMA approvals, due to pending EMA reviews of several compounds. Further, the results of these study endpoints will provide additional understandings of immunotherapy and provide precedence for the future landscape of similar compounds. W 45 Retrospective Chart Review Studies: Key Considerations for Fullfilling Safety Reporting Requirements Dara Stein, MSc UBC: An Express Scripts Company Objective: To highlight main considerations when reporting drug safety outcomes in national and international retrospective chart review studies and describe strategies for ensuring safety reporting requirements are met. Method: Critical review/qualitative analysis of six chart review studies conducted in Canada, the United States, and select European/ROW countries that evaluated drug utilization and clinical/safety outcomes was performed to highlight challenges to safety reporting and strategies for overcoming challenges. Poster Abstracts | diahome.org/DIA2014 36 DIA 2014 50TH Annual Meeting June 15-19 | San Diego, CA Results: Two out of 6 case studies were post authorization safety studies (PASS); one study was mandated by the EMA and one study was non-mandated (imposed by the sponsor). Sample sizes ranged from 200-500 patients; number of study centers ranged from 12-40. Therapeutic areas included oncology, cardiology and infectious diseases. Safety reporting requirements varied across studies. Expedited reporting of safety outcomes (within 24 hours of notification) was required for all 6 studies. Three studies reported non-serious and serious adverse events (AEs/SAEs) documented as being related to the sponsor products as assessed using chart review explicit documentation. Reporting requirements varied for the other three studies. One study reported SAEs documented as being related to the sponsor product; the other study reported all SAEs that occurred while on the sponsor product(s) regardless of documented product relationship. The last study reported all AEs/SAEs that occurred while on the sponsor product(s) regardless of documented product relationship. Reporting requirements were driven by PASS indication, whether the studies were mandated or non-mandated by regulatory bodies, country specific regulations, data being collected and research sponsor standard operating procedure (SOP) safety reporting requirements. European safety reporting directives for noninterventional studies collecting secondary use data are more defined compared with other countries. Expedited reporting posed challenges for regulatory requirements since not all safety data fields were generally completed within 24 hours of AE/SAE notification leaving the safety reporting form incomplete. Safety data discrepancies could not generally be resolved prior to the safety reports being generated; safety reconciliation was therefore challenging. Participating physicians were sometimes reluctant to safety reporting since the AEs/SAEs should have been previously reported at time of occurrence. Conclusion: When safety data are collected in chart review studies, the early delineation of a safety reporting plan is paramount to address ambiguity in guidelines as well as variability in requirements across research sponsor SOPs. More clarity regarding safety reporting directives from regulatory bodies is warranted. DIA 2015 51 Annual Meeting st June 14-18 | Washington, DC DIA 2015 Call for Abstracts Opening Soon! General Call for Abstracts Opens August 4, Closes September 16 Call for Student Poster Abstracts Opens August 4, Closes March 31 New! Call for Hot Topics Opens December 1, Closes January 21 Call for Professional Poster Abstracts Opens January 26, Closes March 3 Visit diahome.org/dia2015 for more information. Poster Abstracts | diahome.org/DIA2014 37
