This article appeared in a journal published by Elsevier. The attached copy is furnished to the author for internal non-commercial research and

Transcription

1 This article appeared in a journal published by Elsevier. The attached copy is furnished to the author for internal non-commercial research and education use, including for instruction at the authors institution and sharing with colleagues. Other uses, including reproduction and distribution, or selling or licensing copies, or posting to personal, institutional or third party websites are prohibited. In most cases authors are permitted to post their version of the article (e.g. in Word or Tex form) to their personal website or institutional repository. Authors requiring further information regarding Elsevier s archiving and manuscript policies are encouraged to visit:

2 Clinical Therapeutics/Volume 36, Number 10, 2014 Commentary The Synergy of the Whole: Building a Global System for Clinical Trials to Accelerate Medicines Development Greg Koski, PhD, MD; Mary F. Tobin, PhD; and Matthew Whalen, PhD Alliance for Clinical Research Excellence and Safety, One Broadway, 14th Floor, Cambridge, Massachusetts ABSTRACT Purpose: The pharmaceutical industry, once highly respected, productive, and profitable, is in the throes of major change driven by many forces, including economics, science, regulation, and ethics. A variety of initiatives and partnerships have been launched to improve efficiency and productivity but without significant effect because they have failed to consider the process as a system. Methods: Addressing the challenges facing this complex endeavor requires more than modifications of individual processes; it requires a fully integrated application of systems thinking and an understanding of the desired goals and complex interactions among essential components and stakeholders of the whole. A multistakeholder collaborative effort, led by the Alliance for Clinical Research Excellence and Safety (ACRES), a global nonprofit organization operating in the public interest, is now under way to build a shared global system for clinical research. Its systems approach focuses on the interconnection of stakeholders at critical points of interaction within 4 operational domains: site development and support, quality management, information technology, and safety. The ACRES initiatives, Site Accreditation and Standards, Product Safety Culture, Global Ethical Review and Regulatory Innovation, and Quality Assurance and Safety, focus on building and implementing systems solutions. Underpinning these initiatives is an open, shared, integrated technology (site and optics and quality informatics initiative). Findings: We describe the rationale, challenges, progress, and successes of this effort to date and lessons learned. The complexity and fragmentation of the intensely proprietary ecosystem of drug development, challenging regulatory climate, and magnitude of the endeavor itself pose significant challenges, but the economic, social, and scientific rewards will more than justify the effort. Implications: An effective alliance model requires a willingness of multiple stakeholders to work together to build a shared system within a noncompetitive space that will have major benefits for all, including better access to medicines, better health, and more productive lives. (Clin Ther. 2014;36: ) & 2014 Elsevier HS Journals, Inc. All rights reserved. Key words: accreditation, alliance, clinical trials, information technology, standards, systems thinking. INTRODUCTION Discovery and development of new medicines, from drugs to biotechnologics, are complicated, time-consuming, and expensive processes, which are becoming increasingly so every year as protocol complexity, soaring costs, widespread delays, regulatory burdens, globalization, and rampant waste pose ever greater challenges. These challenges are not new. They have been recognized and discussed widely for many years, and several well-intentioned efforts have been undertaken in the United States and around the world to better understand them and to identify effective Accepted for publication September 5, /$ - see front matter & 2014 Elsevier HS Journals, Inc. All rights reserved. Scan the QR Code with your phone to obtain FREE ACCESS to the articles featured in the Clinical Therapeutics topical updates or text GS2C65 to To scan QR Codes your phone must have a QR Code reader installed Volume 36 Number 10

3 G. Koski et al. solutions (eg, Clinical Trials Transformation Initiative, TransCelerate, Innovative Medicines Initiative, Multi-Regional Clinical Trials Initiative, Korean National Enterprise for Clinical Trials, and others). In addition, the timing of these initiatives is not accidental. A confluence of new science and technology and concomitantly, regulatory science is driving necessary change. Public health, economic development, and different business models are also critical factors. Any significant change effort in this arena builds on the important roles played by international harmonization and standards efforts. The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), the Council for International Organizations of Medical Sciences, and the World Medical Association (the versions of the Declaration of Helsinki) have provided another piece of the foundation, as have the important standards work of the Clinical Data Interchange Standards Consortium (CDISC), SAFE- BioPharma Association, and OASIS/CareLex, which address data, security, and the Electronic Trial Master File, respectively. Indeed, several thoughtful reports have been published on the subject, offering various recommendations, but few have been effectively realized in practice in large measure because of the complexity of the ecosystem in which these endeavors are conducted and the absence of effective mechanisms, champions, or venues for implementation. 1 4 In part, this complexity is influenced by the sheer number and diversity of stakeholders, which include not only pharmaceutical companies but also regulatory agencies, professional organizations, trade organizations, academic research and medical centers, providers of products and services, research sites, site management organizations, contract research organizations (CROs), research professionals, ethics committees, business management units, patients, advocacy groups, media groups, information technology companies, and more. Although all may share the ultimate goal of bringing new medicines to market in a safer, faster, and more efficient manner, in reality, each has its own interests, some of which are shared and some of which are not. Disparity in interests can impede fruitful collaborations that might otherwise offer effective solutions to many of the challenges mentioned above. Biomedical product development, long characterized by strong financial interests, has become primarily a profit-driven industry. Market forces and a competition-based, rather than collaboration-based, approach to profits have largely driven interactions among these many stakeholders. Consequences of this approach include the creation of proprietary silos and fierce competition among the parties within and between sectors of the industry, the need for intense regulatory oversight, and frequent unfortunate legal and ethical lapses that have undermined public confidence in the endeavor. Once considered to be immune from the effect of such financial interests, academic medical centers have become increasingly entrepreneurial after enactment of the Bayh-Dole Act, 5 and for-profit spin-offs are now commonplace as academic research centers transform themselves to become incubators of product discovery, often in direct collaboration (or competition) with industry partners. During the past decade, the development endeavor has increasingly been recognized as dysfunctional and, more recently, characterized as unsustainable. 6 Calls for disruptive innovation have given rise to a new wave of willingness to consider new approaches and models, including open innovation and data sharing, a host of new strategic partnerships, and the development of new tools and services to promote efficiency and quality, particularly through more effective application of information technologies. 7 Although these activities have fostered some notable successes, they have largely failed to have any consistent, enterprise-wide effect. We believe this is due to a failure to approach the challenges from a whole systems perspective a failure to apply systems thinking. Currently, the medicines development endeavor is strongly influenced by reductionism, which makes sense, given that it is a field rooted in science and thus affected by scientific reductionism. Reductionism holds that complex processes can be understood by breaking them down into their many component parts, the sum of which explains the whole. In scientific fields, 20th-century thinking started to move away from this approach toward an understanding of complexity. 8 Business and organizational thinking, however, even when purporting to move to a systems understanding, 9 is still often rooted in this reductionist approach. Systems thinking, in addition to a focus on components, also recognizes that to understand and work with a system the interconnections among October

4 Clinical Therapeutics components and the purpose of action must be accounted for. 10,11 Organizational theorist Professor Richard Daft describes systems thinking as the ability to see the synergy of the whole rather than just the separate elements of a system and to learn to reinforce or change whole system patterns. 12 He notes that, in breaking a complex process into discrete parts and working to make each part perform optimally, the success of each piece does not equate to success of the whole. Sometimes changing one part to make it better actually makes the whole system function less effectively. According to Daft, systems thinking is a framework for seeing patterns and interrelationships... when leaders can see the structures that underlie complex situations, they can facilitate improvement. But doing that requires a focus on the big picture. 12 Essential to systems thinking, when looking at interconnections, is appreciation of the need for interoperability and interchange among key functional components. No better example exists than in information technology, with its ability to build and use enterprise networks. The Internet itself depends entirely on the ability of various operating systems, software, and databases to efficiently store, access, and share information securely. Such interoperability and interchange are enabled by the development of standards, such as well-known internet transfer protocols (eg, FTP and TCP/IP), without which the Internet as we know it would not be possible. Industries other than the pharmaceutical industry long ago recognized the value and importance of systems thinking and have effectively applied it in their domains transportation, communications, and shipping are well known and proven examples, with none being better known than the global air transportation system. Effective application of systems thinking in these domains has yielded marked increases in efficiency and functionality that have positively affected their business models. In most of these cases, some degree of sharing in the development and use of systems infrastructure has played an essential role in their success. There are also notable instances, such as the cell-phone industry, where inability or unwillingness to share technology platforms and hardware at an enterprise-system level (even when technically feasible) has negatively affected costs and service in some areas. 13 This scenario is reminiscent of the pharmaceutical industry today. Although several entities across the pharmaceutical industry have attempted to apply systems thinking to their own operations and processes, 14 they have not considered the entire medicines discovery and development process as an integrated system. In effect, they have created subsystems that lack connectivity and interoperability. 15,16 Such subsystems can actually create silos that impair widespread utility. 17 When systems thinking has produced significant industry-wide opportunities, such as the CDISC, 18 adoption by the multistakeholder community has been suboptimal, so their full potential remains unrealized. 19 Within the pharmaceutical industry, the value of systems thinking has not been lost completely, but until now there has never been an effort to apply such thinking across the entire enterprise. EMERGENCE OF NEXT-GENERATION THINKING Approximately 2 years ago, after a decade of incubation and recognizing the positive effect but as yet unrealized potential of such efforts as CDISC and ICH, a nonprofit charitable organization, the Alliance for Clinical Research Excellence and Safety (ACRES) introduced the concept of applying enterprise-wide systems thinking to the clinical trials and medicines development process. It was predicated on the conviction that such thinking could provide and implement effective systems solutions industry-wide for the benefit of all stakeholders, including society. ACRES has since established a rapidly growing alliance of like-minded organizations working collaboratively to build a shared global system for clinical research, one that emulates the successful paradigms already adopted and implemented by other global enterprises, such as the global air transportation system. Among a broad group of initiatives currently seeking to promote and accelerate medicines development, ACRES is unique in that it is a multisector initiative operating in the public interest, neither representing nor favoring the interests of any particular stakeholder group. ACRES initiatives are also not intended to augment the competitiveness of any given country or region but rather are global in scope, consistent with rapidly moving trends toward globalization across the industry. Furthermore, ACRES allies are aggressively pursuing comprehensive, enterprise-wide, systems-based solutions rather than 1358 Volume 36 Number 10

5 G. Koski et al. creating limited component-focused solutions on a piecemeal basis. The goal is not to simply select those solutions that are easy to deliver. Instead, ACRES allies are building an open, innovative, comprehensive, shared global system for the benefit of all stakeholders, one that necessarily captures the complexity of the clinical research endeavor. Above all, ACRES foundation initiatives and allies are focused on timely implementation of systems solutions rather than simply offering recommendations. To accomplish this, ACRES seeks to leverage and maximize the full potential of other currently ongoing collaborative initiatives through effective implementation. At an even more fundamental level, the vision and mission of ACRES encompass more than business interests. ACRES is driven by a desire and need to align ethical principles with good scientific and business practices, providing the industry an opportunity to do well by doing good and to restore its reputation and the public s confidence in the enterprise. Many companies within the sector have long-standing commitments to socially responsible business practices, and ACRES provides a practical pathway to fulfilling these societal commitments globally. Concurrently, more effective and universal approaches to ethical and regulatory review and oversight create opportunities not only for simplification but also for true innovation within these domains. IN THE BEGINNING HOW ACRES WAS CREATED Building and maintaining a complex strategic alliance is a significant challenge. Establishing a foundation of committed champions was an essential first step; thus, ACRES began with a meeting of 18 representatives from a variety of organizations who voluntarily agreed to serve on an initial Global Steering Committee that met in Copenhagen, Denmark, in early March 2012 at the DIA EuroMeeting. ACRES founders (Greg Koski, Harvard University; Beat Widler, formerly of Roche; and Andrew Olmsted, Research Dataware) envisioned a global network of highperforming sites of excellence interconnected through a shared information technology platform, with standardized policies and operational procedures and a robust, secure database to support mission critical analysis of performance, quality, and safety within an enterprise-wide culture of safety (Figure 1). With validation of the conceptual framework by a Shared Information Infrastructure and Pharmacovigilance System Global Network of Accredited Research Sites Standardized Policies and Operational Procedures Figure 1. Simple conceptual model of an integrated global system for clinical research. collaborative multistakeholder alliance established, an ACRES executive committee then began building an organizational framework to support and coordinate the many initiatives that would be required. The nascent executive committee identified champions for each operational domain who were appointed vice presidents for each, along with several cross-cutting roles to ensure coordination and integration of activities within a matrix organizational structure. An experienced board of directors was enlisted to provide strategic guidance along with a more tactically focused global advisory board to guide the organization s development. The vision anticipated 4 essential operational domains: site development and support, quality and safety management, safety and pharmacovigilance, and information technology. Whenever possible, a best-of-breed approach of leveraging existing highperforming components and processes seemed to be the most economical, pragmatic, and efficient way to achieve at least an initial version of an effective system. Within each of the operational domains, those components and processes that could be leveraged were identified, and those that would need to be built from scratch were elaborated. The latter included standards and a process for accreditation of clinical research sites, a shared network technology interface, October

6 Clinical Therapeutics along with initiatives to innovatively redesign the existing regulatory and ethics review and oversight processes and to build a broad-based safety culture through application of safety engineering principles and human factors research. With a strong leadership team and organizational structure in place, the next step was to launch the foundation initiatives essential to the creation of the ACRES Global Network. For each, a global multistakeholder Project Steering Committee was empanelled with cross-committee representation to ensure effective coordination. Within a few months, 5 foundation initiatives were under way, engaging dozens of thought leaders from around the world who believed in the ACRES vision and mission enough to contribute their time and expertise. These initiatives included Site Accreditation and Standards (SASI), Product Safety Culture (PSCI, Global Ethical Review and Regulatory Innovation (GERI), Quality Assurance and Safety (QASI), and Site Optics and Quality Informatics (SOQI). At the same time, the leadership began to formalize the ACRES Alliance, a group of like-minded organizations linked through strategic alliance agreements and bringing necessary expertise and resources to bear on a rapidly growing number of projects. The leadership recognized early that within the nonproprietary, nonprofit framework of a shared global systems infrastructure, exclusivity of such strategic alliances would necessarily be limited. Accordingly, the alliance adopted at the outset a set of principles that continue to serve it well integrity, inclusiveness, innovation, and implementation. With the advice of 2 working groups drawn from the members of the original Global Steering Committee, the leadership developed a business plan, value proposition, and list of deliverables, as well as a global organizational framework and development strategy, together with a strategic plan and timeline for development and implementation. The business case and value proposition were, and remain, compelling. The ACRES business modeling indicates that for a one-time investment of approximately US $50 million, an effective global system can be built and implemented in approximately 5 years, becoming self-sustaining in approximately 3.5 years and yielding annual savings of potentially US $20 billion, with the prospect of getting a new molecular entity to market 2 to 3 years earlier than currently achievable. The business model for the CDISC standards implementation, based on the study performed by Gartner, 17 supports these projections; that study found that implementation of the CDISC standards alone resulted in overall 60% savings in the time for study startup, conduct, analysis, and reporting. 18 WELCOME TO THE REAL WORLD CHALLENGES ENCOUNTERED From the outset, ACRES faced 5 critical challenges, and many of these continue, although moderated. These challenges are related to the link between complexity and a global system, credibility, messaging, competitiveness, and funding. The first and perhaps greatest challenge has been to convey to the broad multistakeholder community what it means to build a system, why it is important, and why the current inefficient, dysfunctional fragmented process, although complex, does not qualify as a system. The second challenge was to overcome the justifiable skepticism regarding the possibility of building such a system, given the scope of the project and the complexity of the ecosystem. The third challenge lay in achieving visibility and effective messaging across an ecosystem that has a very high level of background noise. The fourth challenge, common to all transformation efforts, was to overcome inherent resistance to change among well-established stakeholder groups concerned that their positions within the system, even if less than optimal, could be threatened by change. Finally, of course, was the continuing need to generate sufficient resources, both financial and in-kind assistance, to support mission critical initiatives and key personnel. In facing all these challenges, we have come to recognize that persistence is ultimately rewarded and timing is crucial. ACRES has been fortunate in that, whether because of or despite its message, a spirit of collaboration seems to have gone viral in the past few years, in large measure because of recognition that, in many cases, the alternative to collaboration is extinction. Survival is certainly a compelling instinct, even for corporations and organizations, which are, perhaps reluctantly, recognizing, as Benjamin Franklin noted, that We must all hang together, or assuredly we shall all hang separately. Thus, resistance to collaboration, with its ability to solve problems, is decreasing, setting the stage for an acceptable 1360 Volume 36 Number 10

7 G. Koski et al. mechanism for building a global system for clinical research. Conceptually, a systems approach can be difficult to grasp at first. Because the clinical research endeavor is complex, simultaneously addressing all the complexity in words is overwhelming. We have learned in addressing this challenge through much trial and error that the concept and effect of systems thinking can be more easily and effectively conveyed by reference to easily understandable models with which most are familiar. For instance, a picture of a modern high-performance automobile, with its many interoperable smart sensors as an example of applied systems thinking, effectively illustrates how the synergy of the whole is actually greater than the simple sum of the parts and that only when all work together is the ultimate in performance, economy, and safety achievable. Frequently, once the benefits of a systems approach are clear, the next question is, Why didn t we do this years ago? With increasing outreach generating greater familiarity and understanding of ACRES vision, mission, and processes under development, acceptance of the notion of a global system is increasing rapidly. For example, 2 years ago, the global systems concept and site accreditation were viewed by many as a threat to the core activities and business models of CROs. Recently, representatives from top CROs have publically stated that site accreditation will allow them to operate more efficiently and at lower cost to improve their profitability. Indeed, one of the world s largest and most effective CROs (inventiv Health) has recently entered into a strategic alliance with ACRES to support and advance the development and application of standards and processes for site accreditation because they recognize that it is in their interest to do so. Skepticism about the ability to build a global system, our second challenge, has also begun to dissipate as more individuals and organizations, particularly at high levels of the industry, regulatory agencies, and academia, have begun to openly endorse the concept, acknowledging that there may be no real alternative. That other highly competitive industries, such as the international air transportation industry, have been able to build and benefit from their own systems forms a compelling case study and has prompted what Coleridge called a willing suspension of disbelief, even among industry leaders who originally considered the prospect of success not only improbable but impossible. As the message and mission of ACRES have been more widely disseminated through writings, meetings, and presentations around the world and as ACRES achieves progress in its foundation initiatives, the credibility and plausibility of a nonprofit collaborative bringing everyone together to build a global system for clinical research no longer seem as far-fetched as they did 2 years ago. Undoubtedly, meeting the challenge of achieving visibility and effective messaging has been furthered through media coverage of the many press releases that describe key strategic alliances and initiatives, and presentations at national and international meetings have also been important in getting the message out. A recently redesigned website and social media outreach help in this messaging campaign as well ( Organizational support for ACRES through strategic alliances, which at the time of this writing number 65 completed or in the process of finalization, is rapidly increasing. Allies come from every sector of the enterprise, including major companies, professional organizations, product and service providers, regulatory agencies, academic centers, standards organizations, patient advocacy groups, CROs, site management organizations, and site networks, among others. However, the challenge of resistance to change endures and more needs to be done. Some current independent collaborative initiatives working in this area have yet to see the benefit of allying with ACRES, despite efforts to reach out to them. There are also forprofit initiatives operating in this space that may see the nonprofit efforts of ACRES as competing with their interests. ACRES allies, many of whom are forprofit companies, believe that a shared systems infrastructure, standards, and third-party validation of competencies and performance will serve the longterm interests of all stakeholders. The power of the cooperative alliance model may eventually unite all parties, as has occurred to a very large extent in the global air transportation industry, but this remains to be seen. ACRES has also worked diligently to establish relationships with the world s regulatory agencies, and its initiatives seem to be generating interest among them, including the European Medicines Agency, Food and Drug Administration, and Pharmaceuticals October

8 Clinical Therapeutics and Medical Devices Agency, the 3 original ICH members. This is significant because failure to receive endorsement and acceptance by these agencies is mission critical, as has become evident from the CDISC experience. 17 Volunteers and in-kind support are key to the mission effectiveness of all nonprofit charitable organizations, and ACRES is no exception. Addressing the fifth challenge of generating sufficient resources, both financial and in-kind assistance, to support mission critical initiatives and key personnel is, of course, ongoing. On the positive side, nearly 100 global experts and thought leaders are currently contributing their time and expertise to support ACRES mission and initiatives and are implementing the initiatives solutions. The value of technology and services contributions alone currently exceeds US $100 million. Nevertheless, the fifth challenge, the requirement for financial support, is real and often pressing. However, ACRES leadership made a conscious decision at the start to delay formal fundraising until its foundation initiatives were at a sufficiently mature stage to ensure credibility. In addition, ACRES received initial startup funding from a number of private individuals and companies that sustained it through its formative years. In June 2014, the ACRES Board of Directors determined that, building on the progress that ACRES had achieved, it was finally the right time to launch a major capital development campaign, led by Dr Eve E. Slater, a long-time industry veteran (Merck and Pfizer) and former US Assistant Secretary of Health, and Bill Davenhall, head of the Department of Health and Human Services division of the Economic and Social Research Institute, the world s leading geoinformatics company. That campaign, which seeks to raise US $10 million a year for the next 5 years, has already begun to generate major support for ACRES infrastructure, key personnel, and foundation initiatives. In keeping with ACRES public interest mission, balanced funding from a variety of sources for profit and nonprofit will preserve autonomy from influence from any special interest groups. ACRES TODAY INITIATIVES, DELIVERABLES, AND TARGETS During the past 2 years, ACRES has made significant progress and garnered significant support, and its Users Regulatory Agencies ACRES Global Network Patients Providers Figure 2. A shared collaborative global network will be built by the stakeholders in the interests of the stakeholders. ACRES ¼ Alliance for Clinical Research Excellence and Safety. recognition and momentum continue to grow. The 5 foundation initiatives are under way, and a number of related projects are under development as ACRES allies work together to build an integrated global network system (Figure 2). Although it is beyond the scope of this article to describe in detail all the initiatives currently under way, we describe the rationale and current status of some of the highestpriority initiatives at present. Additional information on specific initiatives is available on the ACRES website at Site Development and Support Every observer of the clinical research process has come to recognize what has always been evident but underappreciated high quality research sites matter! Accordingly, much of ACRES initial work has focused on site development and support. The highest-profile initiative in this operational domain, the SASI, addresses the accreditation of clinical research sites. The ultimate goal of accreditation is to recognize and reward excellence. As noted by AstraZeneca s chief medical officer, Dr Briggs Morrison, the industry has failed to properly value and invest in high-performing clinical research 1362 Volume 36 Number 10

9 G. Koski et al. sites. Currently, clinical research resembles a cottage industry at the site level it is estimated that roughly two-thirds of sites never do more than a single trial and most fail to perform according to expectations. Few ever achieve recruitment and enrollment goals, posing an enterprise-wide problem. The value of accreditation of clinical research sites remains controversial in some quarters, where it may be viewed as imposing additional costs, administrative barriers, and potential barriers to entry into the enterprise. ACRES believes that an effective accreditation process must provide incentives and tools to recognize and reward excellence at clinical research sites, enhancing professionalism and sustainability. The dynamic accreditation system and standards being developed by the multistakeholder initiatives of ACRES are intended to ensure that these concerns are properly addressed and that the system provides value to sites, sponsors, CROs, regulatory agencies, ethics committees, and the public. Despite well-established mechanisms for education, training, and certification of clinical research teams, few sites achieve a level of professionalism and performance that enables sustainability. Industry insiders suggest that sponsors would be willing to pay a premium to high-performing, professional sites, and there is little doubt that this investment would provide an incentive to sites to achieve a higher level of performance, serving their own interests as well as those of sponsors and regulators. Accreditation, if performed correctly, provides a proven means for sites to exhibit a long-term commitment to quality, safety, and performance and will allow sites of excellence to be recognized and rewarded appropriately. Performing accreditation correctly requires broad input from the multistakeholder community, and it is this input that is the soul of the SASI. Beginning in early 2013, the SASI follows a carefully laid out approach (Figure 3). Phases 1 and 2 are currently Establish an efficient, effective and representative Project Steering Committee Engage critical stakeholders to champion efforts for site accreditation and workforce certification Conduct broad-based Global Stakeholder Consultation to refine Scope, Strategy and Structure Empower Global Working Groups for Standards and Process Development Develop and Implement necessary standards and agreements Pilot Test and feedback from stakeholders Refine standards and implementation through regional networks Evolving needs of Society and Stakeholders Public Trust Professionalism Quality Assurance Site Performance Risk Management Information Technology Sustainable system infrastructure to drive clinical research quality, safety and efficiency Figure 3. Site accreditation is a fundamental building block of a sustainable, high-performing system for clinical research, one that will also recognize and reward excellence and professionalism at sites worldwide. October

10 Clinical Therapeutics Global Stakeholders Consultation inaugural meeting (June 2014) and online surveys (3 parts). Additional Global Stakeholders Consultations will follow. Planning to appoint Global Working Group and Standards Development teams in July Version 1 of draft standards to be prepared by the end of 2014 for review, feedback, and pilot testing during the first half of Initial phase of accreditation to begin second half of Phase 1 conducted March 2013 to March Working paper in preparation. Phase 2 now under way Phase 3 - early 2015 Phase 4 - mid-2015 Figure 4. Timeline for development, testing, and implementation of global standards for clinical research sites. The standards are focused on promoting professionalism and performance, while ensuring interoperability across the global network system. under way, and the initiative enters the third phase of its work in early In the first phase, a multistakeholder Project Steering Committee initially surveyed the current landscape to identify key issues of concern, common minimal requirements for research sites globally, aspirational goals, and potential performance and quality metrics. A report from the committee describing the findings of this initial phase is currently in preparation, with publication expected in fall The second phase of the initiative, a series of global consultations with key stakeholders, began in San Diego in June 2014 and will continue for the next 2 years. The worldwide Global Stakeholders Consultations seek input from all stakeholders to ensure that the standards and process for accreditation of sites is efficient and effective, meeting the needs and expectations of the various sectors. After the first consultation, in July 2014, the SASI leadership began the process of convening a working party to begin the hard task of developing necessary standards and metrics. Teams of 5 to 7 experts from the global stakeholder community will develop standards in at least 7 domains: personnel, facilities, management, information systems, quality management, recruitment and enrollment, and research integrity. Together these teams will comprise the Global Standards for Excellence Working Party that will be responsible for coordinating the standards development process. Targets have been set for availability of an initial version of standards for review and comment by the end of 2014, initiation of pilot testing in early to mid (phase 3), and beginning of the first round of accreditation in late 2015 to early 2016 (phase 4) (Figure 4). Although this timeline may seem aggressive, it is not unattainable when one recognizes that much of the work has already been performed. Standards and parameters for site qualification and selection are already in wide use by site networks, site management organizations, CROs, sponsors, governments, and professional organizations, many of which are ACRES allies. The standards development teams will draw on, align, and leverage these existing standards and guidelines to facilitate their work. We anticipate a multitiered, phased implementation approach for accreditation. Levels of accreditation will be based on complexity, risk, and specialization of the protocols to be performed at any given site. The value of an accreditation process can only be realized 1364 Volume 36 Number 10

11 G. Koski et al. Global Accreditation Recognition of Excellence Independent Oversight Appropriate Standards Effective Processes Ensure integrity Evaluate effectiveness Must be meaningful Measurable metrics Multistakeholder Minimize burdens Maximize value Neutral third party Figure 5. Required elements of an effective accreditation program. if sites actually seek accreditation, so initial standards, costs, and administrative burdens associated with the process must not be a barrier to entry or participation. Rather, an appropriate and affordable framework to promote professionalism through accreditation will encourage many one and done sites to join a network of sustainable high-performing sites globally, creating a valuable resource for the enterprise overall that benefits all stakeholders, including the sites themselves (Figure 5). Concurrently, ACRES is working with interested parties in the accreditation space to develop an independent entity at arm s length to ACRES that will house and oversee the accreditation process and to maintain and update the standards (Figure 6). ACRES will not be an accrediting body. Accreditation of as many as 150,000 sites globally will require multiple accrediting entities, each of which will require accreditation to ensure the integrity and effectiveness of the accreditation process. The ACRES approach to development of an effective site accreditation process has recently been validated by a joint working group hosted by the Institute of Medicine in the United States under the leadership of Dr Freda Lewis-Hall, Pfizer s chief medical officer, and Dr Clay Johnston, dean of the Dell School of Medicine at the University of Texas. A report from that working group is planned but as yet unavailable. In a keynote address at the inaugural meeting of the ACRES Global Stakeholders Consultation on Site Excellence, Dr Lewis-Hall acknowledged that accreditation of sites is a commonsense approach to improving site performance, one that is overdue, and that mechanisms for recognizing and rewarding site excellence are needed in essence, the time for such accreditation has come and it will be supported by the industry. A Global Network ACRES is working to efficiently build this global network of high-performing sites of excellence by Standards Maintenance Process Manager Oversight and Evaluation Accrediters Accrediting Entity Informatics Figure 6. The accreditation process requires a neutral third-party entity to ensure integrity and effectiveness. All accrediting bodies must themselves be accredited, and information technology must be effectively applied to support the process. October

12 Clinical Therapeutics offering sites that register as ACRES affiliates a menu of tools, products, and services to help them assess and improve their capabilities and sustainability. At the time of registration, sites may select from the menu any of the available offerings for free or at deeply discounted prices, which they deem will offer significant value in return for their commitment to the vision, mission, and values of the ACRES Global Network. This approach allows sites to self-identify their commitment to excellence, affords them enhanced visibility in the marketplace, and prepares them to pursue a path toward formal accreditation. The menu currently includes 17 products and services provided by ACRES strategic allies to help develop and support sites of excellence. Unlike a trade organization or professional society, ACRES is not a membership-based organization, and there are no membership fees charged to sites that choose to affiliate with the network. Tactically, this approach removes barriers to participation and at the same time provides incentives to improve staffing, facilities, and other capabilities, while promoting responsible conduct of clinical research. This is a clear example of systems thinking at work the synergy of the whole exceeding the sum of the parts. Connectivity and Interoperability From a systems perspective, an important requirement of the accreditation standards will be to ensure interoperability across the global network of sites. Toward this end, the standards will incorporate requirements for effective application of information technology at sites, including compliance with existing data standards, such as those promulgated by the CDISC, SAFE-Biopharma Association, and OASIS/ CareLex. It is regrettable and unacceptable in this information age, with robust technology platforms readily available, that any site would still be using paper records. The development of accreditation standards will effectively drive the adoption of these technologies and standards, enabling real-time data capture and interchangeability with attendant benefits to sites, sponsors, CROs, regulators, and other stakeholders. Universal adoption of appropriate information technologies and standards also enables an innovative approach to accreditation, one that we call dynamic accreditation. Traditional accreditation models rely almost entirely on periodic site visits to evaluate compliance with the accreditation standards. We believe this is an expensive, labor-intensive approach with limited effectiveness that is outmoded because it provides only a snapshot in time and no meaningful assessment of site performance. Dynamic accreditation analyzes real-time performance, quality, and safety data according to established metrics to determine whether a site is operating in a manner consistent with the accreditation standards, recognizing that compliance with standards per se is not the goal the goal is performance excellence. This approach applies principles and techniques similar to those used in risk-based monitoring and quality management to identify areas of strength and weakness at individual sites so that this information can be used to continually improve performance. This feedback and adaptive learning mode is a key aspect of a systems approach. When the capabilities of information technology, analytics, and appropriate metrics are combined with judicious use of self-assessment tools and site visits, an efficient and effective process for site accreditation that minimizes administrative burdens and costs will be developed and deployed and will yield significant returns in terms of performance, data quality, safety, and efficiency of clinical trials worldwide. Informatics and Technology The capabilities described above depend on development of a robust supporting information technology platform that can be shared on an enterprise-wide basis. We call this approach site optics, the ability to see what is happening across the system down to the site level in real time. The approach emulates the capabilities established by the global air transportation industry to not only track planes, passengers, and cargo but also collect and analyze operational and safety information on an industry-wide basis to continually improve performance and safety. The SOQI, another ACRES foundation initiative, is engaged in several projects toward this end. As an initial step, several ACRES allies have formed a Technology Consortium to create a shared, universal interface engine that will allow sites, sponsors, CROs, regulators, other providers of products and services, and patients to communicate and collect, archive, and share information in a secure manner. The several members of this consortium each bring existing, immediately available, and proven 1366 Volume 36 Number 10

13 G. Koski et al. technologies and expertise to the table, allowing development and implementation of an integrated interface at a fraction of the cost and time required for development from scratch. The SOQI approach again reveals the value of and ACRES commitment to leveraging existing technologies and capabilities through its multistakeholder alliance approach. The consortium is currently developing models and technical specifications, seeking to complete the initial application for testing and evaluation by the end of 2014, with anticipated deployment in mid In aggregate, the consortium brings enormous expertise, technical capability, and pledges of technologies and services valued at more than US $100 million to the effort. We estimate that the total cost of integrating these technologies into a robust universal platform is ous $10 million. Because the industry is already using these technologies separately to realize significant savings and efficiencies, we can offer them in their present form to companies willing to sponsor the consortium at a significant discount, effectively leveraging the potential savings to financially support the integration-development cost. This approach provides a win-win solution that allows development and implementation to proceed with essentially no net outlay of funds by the sponsors, whereas the consortium members benefit from greater use of their products and services. In the long term, the interface will likely be supported by user fees and other revenue streams related to its use; appropriate financial models are still being considered by the consortium members. A pilot test of this model is now under way with a consortium of small to midsize pharmaceutical companies in Europe to elaborate and evaluate the technological capabilities, economics, and performance effect of the approach. Apart from the development of this interface engine, the system will require secure, integrated, large-scale databases to house and share data to support a variety of innovative functionalities, including safety monitoring, real-time pharmacovigilance, remote risk-based monitoring and auditing, performance and quality improvement, recruitment, enrollment and compliance of patients, and dynamic accreditation. The current trend toward integration of individual electronic health records with clinical trials operations and safety data is likely to accelerate as clinical research becomes increasingly patient oriented, and ACRES is already engaged in several innovative projects with allies, including the Lawrence Livermore National Laboratories, Fujitsu, inventiv Health, and the Swiss Institute of Technology, in anticipation of realizing the full potential of these new capabilities. Quality and Risk Management As the ACRES Global Network of sites increases and the ability to acquire real-time performance and safety information expands, it will be possible to more effectively apply recently developed methods for quality and risk management. One of several projects of the QASI and through the efforts of the ACRES vice president for quality management, Dr Beat Widler, ACRES has developed a proprietary method for audit sharing and monitoring that will be made available to the industry at large through a franchise model that will be managed by a private firm with an arm slength relationship to ACRES. The franchise model will allow ACRES to receive royalties derived from its intellectual property that will provide a revenue stream to support the global system in the long term. Ethical and Regulatory Innovation As this new system evolves, changes in other areas, such as ethical and regulatory review and oversight, will be necessary and welcome. Another ACRES initiative, the GERI, addresses challenges in the regulatory and ethics side of medical research, including the need for ethical and regulatory global standardization, difficulties in complying with complex regulations and guidance, and the regulatory challenge of keeping up with biomedical research and development innovation. The GERI focuses on key elements of the ethical and regulatory review and oversight processes: interactions between regulators and other key stakeholders, communication and cooperation among stakeholders to increase trust, and support for implementation of global innovations and high standards to optimize efficiency. With the ACRES stakeholder consultation model, Ethics and Regulatory Innovation Consultations are being convened, mapping global efforts at regulatory simplification and innovation to derive implementable solutions with ethical review as one point of entry to achieve optimum efficiency in global clinical development. Four implementation-focused working groups October