News Views. Q: What s More Important than Comparative Effectiveness? A: Conducting Effective Comparisons

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1 SUMMER 2010 News Views» Clinical Trials Issue Q: What s More Important than Comparative Effectiveness? A: Conducting Effective Comparisons Just imagine, a health care system that s organized around and finances treatments and interventions that are known to be effective that well designed and properly conducted clinical trials demonstrate that they actually work! That s the motivation behind the Government s most exciting and promising comparative effectiveness initiative. ADVERSE EVENTS LACK OF RECRUITMENT INADEQUATE FUNDING DESIGN FLAW Fifty years have elapsed since an epidemiologist, Archie Cochrane, first proposed this idea in his landmark book Effectiveness and Efficiency (1972). If we are ever to get value for money in health care, then scarce resources must go, not to every promising new idea, but to what is actually effective. And the only way to be certain something is effective, certain enough for the allocation of national resources, is to compare it with something else by conducting a randomized controlled trial (RCT). If effectiveness-based resource allocation is to be an effective policy, then the methodology for the determination of effectiveness how to design and successfully complete RCTs comparing treatments becomes a nationally important issue. RCTs are often difficult to design and challenging to successfully complete. While there are many enthusiastic contestants at the start of the RCT race, only a disappointing few make it to the finish line. Some of NERI s decades of experience with highly successful RCTs is offered to help flagging competitors. Apart from complex scientific design issues, the greatest challenge facing RCTs is the recruitment and retention of study participants. NERI has several decades of successful experience in the design and implementation of clinical trials and can point proudly to its record of effective recruitment and excellent participant retention. TABLE OF CONTENTS: Why Choose NERI? A Pivotal Study for Oncology Patients Requiring Transfusions ADEPT CTMS Improves Efficiency and Quality of Clinical Trials Clinical Research Studies and Patient Recruitment NERI Excels in Patient Registries and Complex Databases NERI Coordinates Two Ground-Breaking Trials

2 Why Choose NERI? A partner with a proven track record of clinical trial success Dedicated and flexible clinical research teams Effective management of networks of clinical sites for challenging indications Proven processes for streamlining the supervision of study sites while enhancing collaboration At the leading edge of development and implementation of a standardized set of metrics NERI is a member of the MCC and is honing a set of operational quality and efficiency metrics to enable continuous and measurable improvement in clinical trial outcomes Transparency to sponsors through real time detailed reports of accrual, retention and site metrics (timeliness, etc) through our ADEPT web-based data management platform Consolidated teams of project managers and data managers who are located at NERI headquarters to ensure that clinical activities for each trial are centralized and streamlined Flexibility to ensure that sponsors requirements are met 25 Years of Best Practices Proven Track Record Dedicated Teams Effective Management Proven Processes Standardized Set of Metrics Transparency to Sponsors Consolidated Teams Flexibility Systematically distilled from NERI s 25 years of experience working with government and commercial sponsors Refined to eliminate the intrinsic inefficiencies that often accompany complex trial execution Streamlined procedures for rapidly moving a project from planning to launch, execution and close-out by keeping our eye on the critical path and ensuring tasks are completed in parallel to the extent possible A system that ensures timely data entry, continual electronic monitoring and immediate, effective remote site monitoring capabilities Start-up strategy assumptions to ensure enrollment projections are aligned with timeline Extensive Quality Control processes built into our systems to ensure a continued high level of quality is maintained throughout trial execution Years of regulatory experience and FDA submissions STATISTICS: In the past 15 years, 96% of trials were completed as designed. In just one year, NERI clinical staff: Managed 491 clinical trial sites open for enrollment Managed 199 registry sites open for enrollment Enrolled 2,196 subjects in clinical trials Initiated 7 new clinical studies and managed 17 ongoing trials and registries Authored 130 articles in top-tier journals NERI s sophisticated clinical trial management system simplifies the management of complex trials and seamlessly integrates multiple functions to enable both NERI and sponsors to transparently track study site activity. In 2008: 117,731 case report forms (CRFs) were entered by sites participating in clinical trials overseen by NERI 1.5 million CRFs were tracked by all currently active clinical studies 44 million data items were collected in the system 2 News&Views Summer 2010

3 A Pivotal Study for Oncology Patients Requiring Transfusions The use of platelet transfusions to prevent bleeding in patients with thrombocytopenia (low platelet count) due to chemotherapy or other causes of marrow suppression is widespread, but a clear consensus of the optimal dose of platelets has been lacking. NERI was the data coordinating center in the Determination of the Optimal Prophylactic Platelet Dose Strategy to Prevent Bleeding in Thrombocytopenic Patients (PLADO) randomized trial, which compared three doses of platelets for prophylactic transfusions in patients with thrombocytopenia due to stem cell transplant or chemotherapy a true comparative effectiveness trial. Key Stats: 1,351 subjects were randomized over 3½ years 26 hospitals in the U.S. participated 95% subject retention was achieved 40% of subjects were women PLADO posed many logistical and clinical challenges. Participants were monitored daily for bleeding assessments, lab tests were conducted daily, and all platelet, red blood cell, and other blood product transfusions were documented. In addition, much work was done to ensure buy-in from the bone marrow transplant group and oncology group at each hospital, and to enroll patients in the context of competing clinical trials. Finally, obtaining truly informed consent was challenging in patients who were coping with overwhelming underlying conditions such as leukemia and lymphoma, the treatments for which can be physically devastating. Results: The primary results were published earlier this year in the New England Journal of Medicine (NEJM, Vol 362: , Feb 18, 2010) and widely cited in other journal articles and oncology-related media. No major differences in bleeding complications were found among the three groups, but more transfusions were given in the lowest-dose group to prevent bleeding. Thus the dose of platelets given by transfusion to cancer patients who become thrombocytopenic could be halved without increasing the risk of bleeding. The significant potential impacts of the study include: changing clinical practice in this patient population; reducing the demand on the blood supply; and reducing costs over the long term. Clinical Trials Issue 3

4 ADEPT CTMS Improves Efficiency and Quality of Clinical Trials Crucial to the success of any clinical trial is the selection of the appropriate platform for data collection and input. Proper electronic data capture (EDC) design can contribute to the success or failure of the trial. NERI s own Advanced Data Entry and Protocol Tracking (ADEPT) system is an example of an EDC system used to plan and implement clinical studies. ADEPT greatly simplifies data collection, while providing a superior and comprehensive platform for the management of sites, clinical supplies, clinical specimens/images, and adverse events. All data keyed by clinical sites is immediately available in the central database enabling sponsors to view standard and customized reports in real-time. Missing data a major issue in many clinical studies is minimized with ADEPT, which automatically checks for illogical, inconsistent or missing data and prompts the user immediately. A typical example of a study coordinated by NERI is the Children s Amalgam Trial a study conducted by NERI with 534 subjects, aged 6-10 years, randomized and followed for 5 years. Missing data in this study was less than 5% of expected data. ADEPT features include: Electronic Data Capture Randomization Biologic Specimen/Image Chain of Custody Clinical Supply and Inventory Control Adverse Event Tracking and Reporting Site Contract and Payment Management Subject Visit Schedule and Task Management Regulatory Document Tracking and Management ADEPT provides: Fast deployment Web-based data entry (no IT footprint) Real-time reporting from the data-base On-line automated edit queries Instant feedback on site performance through automatic protocol adherence Minimal data entry lag and edit resolution Adverse event alerts Extensive support and training Data Security and Integrity 21CFR Part 11 compliance Site Management Real-Time Reporting Customized IVRS/IWRS Customized Pharmacovigilance IVRS/IWRS Web-Based EDC Drug & Speciman Tracking ADEPT fully integrates key activities to ensure seamless coordination between functions. NERI integrates ADEPT into nearly all of its clinical research projects. Sponsors benefit from dynamic, transparent, and cost-effective clinical study management. 4 News&Views Summer 2010

5 CASE STUDY #1 Project VIVA A ten year longitudinal study of children has changed with each new funding cycle. Throughout the course of this study data have been collected on paper, via EDC, through electronic uploads from central laboratories and via a Computer Aided Self Interview (CASI) interface. All data have been seamlessly combined in the ADEPT database. CASE STUDY #2 Global Congestive Heart Failure Study Details: Phase III, Randomized, Double-Blinded, Placebo- Controlled study 3,515 subjects 220 clinical study sites 6 countries (North America, Eastern Europe, Latin America) Drug product by lot number and matches to every randomized subject Key ADEPT Highlights: Drug inventory management that tracks Drug and subject blinding and randomization (IVRS / IWRS) management Biologic specimen chain of custody tracking and reporting for a biorepository Site payment management based on milestones Adverse Event and study outcomes automated reporting to the Medical Monitor Detailed subject and site status reports CASE STUDY #3 Proactive Proactive Accrual Monitoring A large NERI trial in Sickle Cell Disease concerned with overall accrual is able to keep abreast of targets and enrollments using ADEPT s standard accrual graph. Recruitment: Count Percent of Planned Accrual Period Elapsed 25% 50% 75% 100% 75% 50% 25% Recruitment: % of Target (300) 0 Jul 09 Aug 09 Sep 09 Oct 09 Nov 09 Dec 09 Jan 10 Feb 10 Mar 10 Apr 10 May 10 Jun 10 Clinical Trials Issue 5

6 CASE STUDY Clinical Studies in Children Children and Clinical Studies is a campaign targeted to parents who have been asked to enroll their child in a clinical study. This set of tools includes a web site for parents, print materials for pediatric offices, and DVDs including documentary discussions with parents and experts. The website combines practical information with awardwinning video footage of children, parents, and healthcare providers discussing the rewards and challenges of participating in research. It includes the important perspective of a parent s choice not to participate, stressing that such decisions be made based on information rather than fear. The site describes why research in children is important, how studies are conducted, and what measures are taken to protect participants safety and privacy. This program was developed by NERI in collaboration with NHLBI and Hands On Productions. WATCH th e V IDE O In English and Spanish Start Here Running Time is 23 minutes No More Hand-Me-Downs: Research Designed for Children A documentary offering facts and insight into why children should be included in research and educating families about participating in studies. SE AR CH CLINI CA L RE DESIG NED FOR CHI LDR EN Clinical Research designed for C hildre Clinical Research in Children? Go online to learn more. WATcH the informative video to learn more. Go to Watch the informative video to learn more. Join experts, parents, and children as they discuss their experiences with clinical research and answer a variety of important questions. Talk with your healthcare provider Explore whether a research study might be a good choice for you and your child. Join experts, parents, and children as they discuss their experiences with clinical research and answer a variety of important questions. TaLK with your child s healthcare provider. Ask how research can improve health through treatments and medicines designed especially for children. EXPLORE if joining a study might be right for you and your child. Clinical Research Studies and Patient Recruitment Clinical research saves lives and improves public health and well-being. This research depends critically on the participation of patient populations relevant to the medical treatment, devices or medications being studied. NERI researchers have worked hard for more than two decades to understand how to improve the education and, thus, recruitment efficacy, of participant populations. This long-standing goal has resulted in an array of tools designed and developed by NERI to help inform and educate potential research participants. Our work combines well-known technologies such as DVDs, web sites, and print materials, but goes beyond simply designing an interesting education campaign. Our in-house qualitative experts conduct focus groups to understand which communication tools are most relevant to a given population, whether there are specific language or cultural issues to address, and which messages about a study are most relevant to the audience. 6 We don t stop at recruitment. We have some of the highest retention rates for long duration studies at least 90% for the majority of studies completed in the last two years. Participants are often engaged in research for long periods of time, so we work hard to provide information throughout their participation, even through simple gestures such as birthday cards, or (where possible) through letters providing basic lab results or interesting information about the research to which they are contributing. We also understand that clinical studies don t occur in a vacuum participants belong to communities and organizations relating to their conditions. We therefore work with these groups to better understand the needs of patients and potential obstacles to their participation in studies. News&Views Summer 2010

7 NERI Excels in Patient Registries and Complex Databases Patient registries have evolved from simple lists of people with specific medical conditions into complex databases that carefully monitor disease states and track outcomes of medical interventions. Today s patient registries, whether disease-based, or product-focused, are vital resources for capturing real-world patient information. NERI registries achieve multiple scientific, commercial, and regulatory goals to provide: Much needed information on the natural history of diseases or rare conditions The Pediatric Cardiomyopathy Registry (PCRMR) is a North American registry of more than 3,500 subjects that collects incidence data, management practices, and outcomes for children with this disease. Key questions that the registry is designed to answer include: What is the natural history of the disease? How is cardiomyopathy managed? How are patient factors associated with long-term outcome (mortality and heart transplant)? Post-market surveillance to meet regulatory requirements NERI s 522 Registry, collected 5-year outcomes on device performance, safety, and efficacy. Data to meet reimbursement requirements of the Centers for Medicare and Medicaid Services (CMS) NERI s SVS Vascular Registry on carotid procedures currently has over 14,000 patients with long term follow-up and is used by CMS for recertification of facilities. A source of potential patients for clinical trials, which speeds recruitment NERI s Thalessemia Registry, part of the Thalessemia Clinical Research Network, tracks patients at participating clinical centers who might be eligible to participate in future trials. NERI understands the rapidly expanding need for patient registries. We provide sponsors with in-depth expertise in the creation, coordination, analysis, and management of large, and often disparate, datasets. NERI is experienced in combining data from active registries and clinical trials into a single registry with ongoing patient follow-up for long-term safety and effectiveness. Measures of patient-reported outcomes, quality of life, and cost-effectiveness NERI s Post Traumatic Stress Disorder registry collects patient reported outcomes in a veteran population. Clinical Trials Issue 7

8 NERI Coordinates Two Ground-Breaking Trials Comparing Outcomes of Standard of Care Surgeries Urinary incontinence is one of the most common chronic health conditions in the U.S., affecting between 15% and 50% of women, with incidence rising with age. Over 100 surgical procedures have been described for treating stress urinary incontinence (SUI), a type of urine leakage associated with activities like coughing, sneezing, laughing, or exercising. NERI has coordinated two ground-breaking, multi-center, randomized, controlled clinical trials that compared standard-of-care surgeries for SUI. These studies were the first to directly compare outcomes of these surgeries in a rigorously controlled randomized study. KEY FACTS: Enrolled patients at 34 clinical centers Subject enrollment was completed within 2-5 months of target date (100% women) Retention: 95% at 12 months for both trials and 87% at 24 months for SISTEr. Rigorous quality control to ensure standardization of surgeries, critical clinical tests, and procedures Automated randomization in operating room Subjects randomized after anesthesia to minimize pre-operative drop-out Standardized coding of surgical complications and adverse events The SISTEr trial compared two gold-standard surgeries, the Burch colposuspension and the autologous rectal fascial sling. The subsequent TOMUS trial compared two more recent and widely used minimally invasive mid-urethral slings, the retropubic (TVT) and transobturator (TOT) slings. A superiority design was used in the SISTEr trial to determine if one surgery was better than the other, whereas an equivalence trial was used in the TOMUS trial (NEJM Vol 362: , June 3, 2010) to determine if the two surgeries achieved equivalent results. 9 Galen Street Watertown MA media@neriscience.com neriscience.com