CDISC Journal. Organizing and Accelerating the Clinical Research Process from the Beginning: The CDISC Protocol Representation Model and Toolkit

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1 CDISC Journal Clinical Data Interchange Standards Consortium oc tober 2012 Organizing and Accelerating the Clinical Research Process from the Beginning: The CDISC Protocol Representation Model and Toolkit By Andrea Vadakin, Manager of Public Relations, CDISC Brooke Hinkson, Associate Director of Program Management, Global Biomedical Informatics, Genzyme Corporation Members of the Protocol Representation Group Overview What is the Protocol Representation Model, and how does it affect the success of a clinical study? As we will see in this article, the Protocol Representation Model, or PRM, is of great importance, not only to data managers and statisticians, but to individuals and entities across the realm of clinical research: from the clinician, to the medical writer, to the study coordinator, to federal agencies, and eventually and most importantly, to the patient. The PRM was developed to a) support the generation of a protocol document, b) to support research study (clinical trial) registration and tracking, c) to support regulatory needs, and d) facilitate single-sourced, downstream electronic consumption of the protocol content. This article offers background information on the history of the Protocol Representation Model and generation of PRM V 1.0, recent developments in the model, use cases for the PRM describing the business value of the PRM, description of a new Toolkit made available to users of the PRM and anticipated future progress in this area. The Clinical Research Study Protocol As researchers know, the protocol, in terms of a clinical research study, is the plan, or blueprint, that describes the study s objectives, methodology, statistical considerations, and the organization of the study. Much in the way that an effective business plan lays out the foundation for what is expected in beginning a successful enterprise, a well-designed protocol is the map that is vital to the overall success of a clinical trial or study. Everyone involved in the research study needs the protocol; this includes but is not limited to the investigator, the site personnel, the clinical project managers and monitors, the data managers, and the statisticians. Additionally, the protocol is a requirement by regulatory authorities for regulated clinical research studies. A fully developed clinical protocol is essential for regulatory purposes including Investigational New Drug (IND) applications and for Institutional Review Boards (IRB) and Ethics Committees. 1

2 The problem with the typical protocol document is that it is not in a useful format for information management and e-use. The current standardization often amounts to little more than the specification of font and type size in a Word document (see Fig. 1). Once written, the protocol has many users, who extract information from the protocol to: Educate investigators and site personnel on the study plans and requirements; Enter into trial registries like clinicaltrials.gov, EudraCT (EMA) or the World Health Organization s (WHO) International Clinical Trials Registry Platform (ICTRP) and other study tracking systems; Create case report forms using the CDISC CDASH standard; Input into CDISC Operational Data Model (ODM) or similar format for data collection in EDC systems (e.g. ecrfs based on CDASH and PRM) and data archiving purposes; Set up database tables, including Study Data Tabulation Model (SDTM) datasets for electronic submission of the clinical trial information to the U.S. Food and Drug Administration (FDA), e.g. Trial Summary at the start and data from the study at the end; Re-use of protocol information in the final clinical study report. Since few if any of these protocol extract-and-reuse processes are currently automated, this is all incredibly time-consuming for the protocol many users. In addition, many users need only a small part of the information in the typical page protocol document, so the document is ponderous to read and interpret, at best. Fig. 1: This is the typical current state of standardization of a protocol document. Ensuring that all clinical research protocols meet a minimal set of requirements (based upon ICH Guidelines and Good Clinical Practices) and provides tagged informational elements that are machine-readable allows for automated re-use and re-display of this information in multiple ways and 2 CDISC.org

3 encourages compliance through traceability. For instance, the study plan/design can be summarized in a form that is easily understood by reviewers, including a governing regulatory authority, IRB or Ethics Committee, promoting a more efficient and higher quality review. The Protocol Representation Model (PRM) is the foundation for such a machine-readable protocol. The Protocol Representation Model (PRM)¹ The primary motivation for developing the PRM grew from the recognition that the protocol is the core to every clinical research study. Given this importance, the protocol holds the most critical pieces of information to standardize in a machine-interpretable format. PRM effectively standardizes the content, allowing for a large set of some 300 agreed-upon standard concepts, such as the trial objective and phase, to be represented and structured in such a way that the resulting document is easy for a researcher to understand, while also enabling the easy exchange of protocol content across systems basically, ensuring that the protocol information be utilized in multiple ways without re-entry (See Fig. 2). Fig. 2: Structuring information within a protocol can enable re-use, thus streamlining protocol use. In the top representation, the protocol information is identified whereas in the bottom it is depicted in a way that will enable tagging elements with metadata (data about data) and enabling re-use in electronic tools and with XML. The PRM models a common structure for protocols that can be used to streamline the creation, maintenance, sharing and reuse of the information in a protocol by breaking it down into standard, machine-readable components that can be electronically stored in a database. This does not in any way compromise flexibility of the content of the protocol or the design of the study; rather, it structures 1. For a detailed Protocol Representation Timeline, please see Appendix I. 3 CDISC.org

4 components by identifying them as common across protocols and thus candidates for re-use. These components can then be updated, shared across disparate systems and maintained independently of each other. In addition, a protocol can be generated that is also human-readable for all users of the document. The practical benefit is that developing and maintaining protocols becomes less time consuming and expensive. Moreover, as the PRM defines the elements of a protocol and then (through UML modeling) represents relationships between them, it is now easier to find key elements that are usually hidden within lengthy textual descriptions. Essentially, the PRM provides common labels for these key elements so they can agged (e.g. through an XML schema) and then electronically searched and read by a computer. The protocol information can then be readily entered into an information system or online registry that allows key protocol information to be searched, entered and stored in a database, shared, analyzed, reported on and reused. This supports a range of important clinical research goals, such as increasing transparency in clinical research, providing patients with the ability to find studies in which they are eligible to participate, adhering to study registry requirements, populating study management/tracking systems, sending information to IRBs or Ethics Committees, providing FDA with Study/Trial Summary and Study Design information, and writing post-study clinical reports. A timeline with milestones for the development of the PRM is shown in Appendix I. The figure below (Figure 3) depicts the main sections of the protocol that are included in PRM v 1.0 and the main activities that the PR Group engaged in to develop v 1.0. Fig. 3: Major milestones and protocol sections included in the development of PR V 1.0 by the Protocol Representation Group. 4 CDISC.org

5 Recent Developments to Support Use of PRM After seven years of effort by a multidisciplinary team initiated in late 2002, PRM version 1.0 was released in early While the release of version 1.0 of the PRM was a major achievement, its UML modeling language format (the modeling approach of the BRIDG model was found to be too technical for ready use by certain target audiences. Medical writers, clinicians and study managers, who are not typically experts in modeling language, found PRM V 1.0 overall to be too difficult to understand and use. To assist the end-user, CDISC is now, through contributions of the PR Group, providing a toolkit initially focusing on a PRM Study Outline, utilizing approximately 30 basic concepts that should be found in any protocol (including applicable aspects of the Trial Summary (TS) domain of SDTM), all organized into a Microsoft Word template. This outline template will produce a short document which includes the key information needed in the early development of a protocol, added Diane Wold, Director of Data Standards at GlaxoSmithKline and long-time Protocol Representation Group (PRG) member. These elements are also among those most re-used later in the protocol life cycle. In addition, CDISC Protocol Representation Group (PRG) is seeking to simplify this process even further through the creation of a Protocol Representation Model Tool. This is represented in Figure 4 as the current step for the PR Group. Fig. 4: This figure shows the primary areas of focus from the beginning of the PR Group to the release of PRM Version 1.0 in 2010 through the release of the initial Toolkit in Output during 2012 will include support for the generation of SDTM Trial Summary domain content. PRM Use Cases: Study Outline Concepts Defined During Study Design Phase Enable Streamlined Business Processes If we apply the same scrutiny and attention to detail of what is authored in a clinical synopsis and protocol to the information (content) itself, one can recognize the downstream re-use of the information and the value of incorporating industry standards up-front during the study design stage of a research study. The CDISC Study Outline Concepts contain an essential set of study design concepts that are defined during the study design stage of a clinical trial and re-used across the clinical lifecycle by 5 CDISC.org

6 various stakeholders. Ensuring that Study Outline Concepts and supporting controlled terminology are incorporated into the synopsis and subsequent protocol streamlines multiple business processes. The following are examples of how business processes can be streamlined via using and reusing the Study Outline Concepts. Streamlines the Creation of the SDTM Trial Summary Dataset By using the Study Outline Concepts at the time of synopsis and protocol authoring approximately 65% of the Trial Summary elements are defined. 21 of the 35 Study Outline Concepts directly map to the SDTM Trial Summary Dataset 6 of the possible 18 required trial summary elements that can be defined before study start are contained within the Study Outline Concepts Additionally, 5 conditional elements (elements classified as if applicable or conditional ) are also defined in the Study Outline Concepts Compliance with Clinical Trial Registration and Results (CTR&R) Incorporating the Study Outline Concepts into the synopsis and protocol streamlines the mandatory CTR&R reporting for the registries around the world (e.g., ClinicalTrials.gov and EMA s EudraCT and WHO s ICTRP). 25 of the 32 Study Outline Concepts and their associated controlled terminology that are included within the protocol synopsis are also re-used to fulfill protocol registration requirements Sponsor Internal Review of Study Design Poor study design can result in clinical study timeline delays, protocol amendments, increased cost, and even the inability to successfully evaluate the study endpoints to determine if the study objectives were achieved. Therefore, incorporating the Study Design Concepts into the synopsis is critical to ensure: The study is well designed: Example questions asked to evaluate the study design include: Is the patient population appropriate? Do the inclusion/exclusion criteria allow selection of patients to reach the defined endpoints in the intended timeframe? Are we collecting the appropriate amount of data (not too much or too little), to achieve the study objectives? The study is operationally feasible: Is the burden to the patients acceptable? Is the site burden reasonable? Costs are not unnecessarily inflated: Are the costs associated with the trial reasonable? Do the assessments align with standard or care; will there be additional costs for performing the assessment as defined Schedule of Study Events? Regulatory Review of Study Design In order for regulatory authorities (such as the FDA) to reliably and effectively review protocol information, they need standard content in a consistent format that will be provided by all Sponsor 6 CDISC.org

7 companies. Incorporating the Study Outline Concepts into the synopsis and protocol enable straightforward discussions with regulators regarding study design early in the development process. Pre-IND Meeting, Study Design Review: FDA encourages Sponsor companies to have discussions with FDA regarding a planned study early in the development process. Ensuring that the synopsis contains the Study Outline Concepts standard will provide the necessary trial design content for review and facilitate the overall discussion regarding study design. The use cases described above illustrate how applying the Study Outline Concepts at the time of synopsis development (i.e., early in the clinical development lifecycle) benefits sponsor companies by better facilitating internal and external study design review, as well as ensuring downstream alignment with SDTM Trial Summary and Clinical Trial Registration & Results (CTR&R), as well as enabling re-use of the information and streamlined business processes. Ensuring that all protocols submitted to the FDA are in a standard format decreases the amount of time spent in review, and assists in accelerating the drug development lifecycle, of major concern to patients. From the FDA s perspective, the review of clinical trial protocols remains a very manual process, stated Dr. Armando Oliva, Senior Biomedical Informatics Advisor for the Center for Drug Evaluation and Research (CDER) at the FDA. What the CDISC standard for representing a protocol provides is helping the FDA take the first step in improving how protocol information gets reviewed. The FDA has been extremely supportive of the CDISC standards in general, which includes the development of PRM and, in particular, the Trial Summary Domain for SDTM. The PRM Toolkit The next exciting step in effectively simplifying and encouraging a more efficient process to clinical research is the PRG s first release of the new Protocol Representation Model Toolkit now available. The current release published a standard Study Outline Microsoft Word Template, a standard list of Study Outline Concepts, and a complete mapping of the Study Outline Concepts to both BRIDG and the SDTM TS Domain. These are published on the CDISC website in the Members Area. The next release of the Toolkit in 2012 will include the PRM Protocol Wizard. The Wizard will allow the end user to simply plug and play different protocol elements into a simple-to-use XML form. Rather than writing out each part of the protocol outline, the form prompts the author with specific step-bystep concept inquiries, such as in what phase is this trial? The author can then enter the specified fields, and the form will generate a protocol study outline. Even more, the tool will potentially have the ability to output not only the protocol document, but create the SDTM Trial Summary Domain. Further developments planned include generating a trial registry message to populate a clinical trial registry. What once took hours to reengineer into different formats now requires only a few button clicks Another possible feature includes allowing the author to ensure completeness up-front, guaranteeing that all variables that the FDA might require are accounted for prior to submission. The Protocol Representation Group: Multidisciplinary Support for and Contributions to the PRM From the industry perspective, application of the Protocol Representation Model from the initial stages of clinical trial planning can save significant time and effort. The Protocol Representation Group itself is composed of committed CDISC member organizations across the healthcare industry. A representative 7 CDISC.org

8 of Medidata Solutions serves now as the lead on the PRG; his company is providing the tool at no cost to CDISC, and many of their clients, along with organizations such as Genzyme, Digital Infuzion (who sponsored the documentation for PRM V 1.0), the National Cancer Institute (NCI) and City of Hope (a California-based cancer hospital), are already utilizing the Protocol Representation Model for different purposes in their research processes. City of Hope (as reported at AMIA 2010) uses PRM elements (eligibility criteria) in order to match patients to research protocols, to keep track of trial progress and to compile protocol information into a repository. Employment of the PRM structure for describing research studies ensures that the information in the protocol is consistent with industry standards. The European Medicines Agency was an initial participant in the PR Group with an expressed interest in ensuring that EudraCT and the PRM elements for trial registry stay in sync. And, it was an FDA representative who helped initiate the Protocol Representation project. The National Institutes of Health (NIH) have also showed avid interest in the development of the PRM. In fact, certain sections of the PRM are harmonized with the NCI s Study Calendar, and the Trial Registration section supports registration into National Library of Medicine s clinicaltrials.gov and the WHO International Clinical Trial Registry Platform. Reviewers of the PRM have included key members of the American and European Medical Writer s Associations (AMWA, and EMWA, respectively). There is significant potential value for medical writers, with respect to their contributions to protocol and clinical document authoring. As users of protocol information at both the front-end (protocol) and back end (clinical study report), medical writers appreciate the value of a PRM tool that provides accepted standards of structure and defined terms, added Arthur Gertel, Vice President of Strategic Regulatory Consulting, Medical Writing and Quality Assurance for Beardsworth Consulting and PRG Member. The Protocol Representation Group has been a dedicated volunteer group that has changed over the years as its members grow into new jobs and other interested participants join the group. It was initiated in 2002 with leadership from the FDA and CDISC. The list below depicts contributors to the PRM over the years, and this is certainly not complete (See Fig. 4). The first step of this group was to explore ICH E3, E6 and E9 and other global protocol requirements to develop a spreadsheet with an outline, hierarchy and elements that are common across protocols and to test this with numerous protocols. This work has now progressed to the current stage where it is hoped that all stakeholders can use the PRM (Please see also Appendix II for specific acknowledgements). Fig. 4: Current and Former Participants in the CDISC Protocol Representation Group 8 CDISC.org

9 The Future for the PRM The expected outcome of both the Protocol Representation Model and its associated tool is to leverage technology in such a way as to streamline aspects of the protocol development process and evaluate the internal integrity of a protocol before submission (to an IRB or Ethics Committee or regulatory authority), while ensuring that the resulting document is both machine-readable and human-readable. This allows the protocol to be used more effectively downstream and drives future retrospective research from integrated data warehouses. Using PRM from the outset of the clinical trial development process ensures that the development and maintenance of protocols is less time-consuming and expensive, as well as ensuring a quicker and more efficient review process. As with all of the CDISC standards, the PRM is constantly being updated and developed. While the PRM Tool currently serves the purpose of generating a Study Outline based upon standard protocol concepts, next stages of development will broaden this list. The Protocol Wizard will build upon this initial Toolkit. Perhaps someday a tool may be created that can provide the full list of protocol concepts in a form that will allow key protocol stakeholders to appreciate and benefit from the PRM. This new Protocol Representation Model tool is just a first step in this process. In order to reap the full value of the PRM and new tools for users will require a change in mindsets and processes of those involved in the early stages of protocol development. While there is no intent to modify or diminish creativity that must be funneled into a new direction to fully leverage the newly available technology at this stage. A partnering of the technical skillsets with the clinical expertise will provide the optimal opportunity to benefit from the efficiencies of re-using information from the beginning to end of the clinical research process. As the complexity of research and study design increases, this will business process value will be essential. 9 CDISC.org

10 Appendix I: The Protocol Representation Timeline 10 CDISC.org

11 Appendix II: Acknowledgements With the release of this article, we would like to take this opportunity to thank the many dedicated individuals and organizations whose tireless efforts have enabled the development of the PRM version 1.0 and the first release of the PRM Toolkit. Our sincerest thanks specifically to Dave Gemzik (PR Group Leader), Art Gertel, Diane Wold, and Brooke Hinkson, in addition to many others for their continuous support of CDISC and their assistance in the release of this document. Copyright CDISC October 2012 cdisc.org 11 CDISC.org