Why a Common Protocol Template? November 2018

Why a Common Protocol Template (CPT)? Patient Advocate “Just because ‘subject’ is in the regs, doesn’t mean you have to use it. Patients think of ‘subject’ as a verb, and who wants to be subjected to something? Please use ‘trial participant’ instead.” FDA “If you have standards without traceability, then you aren't really CDISC compliant.” Investigator “Patient recruitment is challenged by the complexity of protocols. Sponsors do the same things too many different ways. Just make it the same!” Legally approved 4-Oct-2018 Let’s start our discussion by looking at the drivers for a common protocol template – Why did we set out to create the CPT? At many meetings, for some time, we had been hearing a variety of voices commenting on how Sponsors design and implement trials. This slide summarizes some specific input heard at a DIA meeting in 2015. Investigators spoke of the increasing complexity of our protocols and the fact that every Sponsor seems to do things differently. This further complicates study execution for any site who is working with multiple sponsors. <TRIGGER ANIMATION> Sometimes a simple choice of words can also be of concern. We heard from patient advocacy groups that there was a sensitivity to the use of the word “subject” in many protocols. This reminded us that the trial participants themselves would also be a key stakeholder group to be considered. A key Health Authority perspective was expressed by an FDA colleague, who reminded us that we would need to go beyond modeling common text. To achieve CDISC compliance, we would need to ensure end-to-end traceability of data from source to final datasets. Heard at a June 2015 DIA meeting…

Background: Why a Common Protocol Template? Problem Statement Format and core content of study protocols vary from sponsor to sponsor making interpretation difficult for study sites, IRBs, and regulators. Study protocols have become increasingly complex and lengthy driving up cost and time. Manual set-up of clinical systems based on non- standard “manual” protocols is time consuming, costly, and prone to error. Solutions Develop a streamlined model clinical trial protocol, including format and core content, to ease interpretation and enable down-stream automation of many clinical processes. Develop model protocol endpoint definitions, incorporate into piloting of the template. Legally approved October 2018 Guiding Principles “Common” in a CPT: information always in the same place, means the same thing. Is it better? Move beyond incremental improvements and current limitations. It has to be better for everyone, but Investigators/Sites are the first priority. A human readable template that paves the way for an automated solution and facilitates the use of data standards.

The “Must Haves” in development of the CPT Structure must… Be streamlined Be consistent Content must… Develop common wording Align with GCP, ICH, & EU requirements Allow for all phases and study types Endpoints must… Map to an objective Support use of CDISC TA Standards “Just make it the same!” - Investigators and Site Coordinators of the SCRS Site Advocacy Group pled for consistent organization of protocols across sponsors Metadata Traceability Reuse Automation Anchors Legally approved October 2018 From the start, the Common Protocol Template team has maintained a keen focus on a few key “must have” elements or characteristics. We believe that this focus is what differentiates this initiative from past efforts. The team sought to develop a streamlined and consistent structure, with model wording that is compliant with GCP and regulations. We heard of this need, loud and clear, from the investigator and site coordinator community. Endpoints were another area of focus, and the CPT team set out to ensure that each endpoint is mapped to a trial objective, and aligned with CDISC TA standards where appropriate. Beyond the template itself, and with a future automated state in mind, all initiative work has been grounded in the four anchors shown on this slide: Metadata, Reuse, Traceability and Automation.

The Common Protocol Template Potentially Benefits Many Stakeholders Near Term Benefits to Sponsors Reduction in redundant protocol content Enabling of therapeutic area standards Improved conduct of the study and quality of data collected Near Term Potential Future State Potential Future Benefits to Sponsors Automation of downstream processes and reuse of content Enabling of therapeutic area standards in additional TAs Enabling collaborative clinical trials Potential Future Benefits to Regulators Increased ease of data interpretation and ability to compare protocols (improves input on protocol design), Increased use of data standards enabling end-to-end use of metadata and traceability Sponsor Sites IRB Patient Regulator Near Term Benefits to Sites Protocols streamlined and organized with an investigator focus Reduced burden on sites working on multiple studies Near Term Benefits to Regulators Protocols streamlined, increased consistency between sponsor protocols to ease review Legally approved October 2018 So, we set out to develop a Common Protocol Template that would offer benefit to a number of stakeholders, both in the near term, and also into the future. <TRIGGER ANIMATION> Starting with the Sponsor, a common template could reduce redundancy, and drive therapeutic standards, thereby enabling operational efficiency and improved data quality. Over time, model content could be reused to automate downstream processes, and would also enable improved collaboration across Sponsors. Sites would immediately recognize streamlined and better organized protocol content, and see a reduced burden when working across multiple studies. In the future, a common protocol template could allow for harmonization of other site documents and processes that stem from the protocol. Institutional Review Boards or Ethics Committees would enjoy the same benefits as the sites. Finding the same information in the same location in protocols written across multiple sponsors could facilitate their review of protocols. Over time, harmonized structure and model content would also support easier automation of IRB submissions. From the patient perspective, some of these immediate benefits to sites and IRBs would translate to increased efficiency in study start-up and improved quality in ongoing trials for participants. In the future, the automation of downstream processes beyond the protocol could allow Sponsors to get medicines to patients faster. Finally, Regulatory authorities will see near term benefits in terms of streamlined and more consistent protocols that are therefore easier to review. Over time, more commonality and increased use of automation and data standards will enable easier interpretation and comparison of results, and could allow for more efficient reviews. Potential Future Benefits to Sites Opportunity to harmonize additional documentation Enable consistency of some case report forms Potential Future Benefits to Patients Improved access to protocol information Getting medicines faster, for participants & future patients Near Term Benefits to IRBs Increased consistency between sponsor protocols: easier review and faster approval Near Term Benefits to Patients Increased efficiency / quality in clinical development for participants & future patients Potential Future Benefits to IRBs Enabler for automation of IRBs submissions

Common Protocol Template is Intended to Prepare for the Future State Foundation Future Human- Readable Protocol Disclosure SAP CSR IRB/IECs Sites Regulators Machine- Readable Protocol Content Reuse Metadata driven processes eCRF Statistical Output A common protocol template structure with harmonized language Streamlined content enables identification of critical information for end users Begin working towards model endpoint definitions to align with Clinical Data Interchange Standards Consortium (CDISC) Therapeutic Area (TA) data standards. TA Libraries available Reconnect processes (protocol, eCRF, development) Transformation of the design process Analytics-driven trial design, modelling, scenario planning Role-based access to protocol information (Principal Investigator [PI], Ethics, Participants) Connection to other systems Legally approved October 2018 Progress to date on the CPT includes the development of a human-readable template document. This will enable sites, reviewers, ethics committees and regulators to find the same information in the same place and have it mean the same thing. <TRIGGER ANIMATION> The template consists of a core of model content supported by a series of libraries appropriate for a given study type or disease area. Critical protocol level content has been aligned to the data standards project which is a collaboration between TransCelerate and Coalition for Accelerating Standards and Therapies (CFAST). The alignment of objectives, endpoints and procedures is a critical element of the document-based solution. This template paves the way to evolving to a machine-readable protocol where content is reused, and metadata drives downstream processes, introducing the possibility of establishing the protocol as a digital platform with analytic trial design, role-based access to protocol information, etc. In both the document based environment as well as the digital environment it will be critical to reconnect certain processes and develop critical study components in parallel rather than serially (e.g. eCRF, Statistical Analysis Plan –SAP) At this time, the template core will support trials in any Therapeutic Area. As a first step toward enabling data standards, disease specific libraries have been created, with common endpoint definitions based on the CDISC Therapeutic Area User Guide (TAUG).

The Common Protocol Template is NOT…. A training document for protocol writing teams. A training document for inexperienced sites. A document for internal contracting of downstream actions within the sponsoring organization. An enrollment feasibility document (specifically referring to the Synopsis section). An exposition of the Sponsor’s development program. A substitute for or duplicate of the Investigators’ Brochure or Statistical Analysis Plan (SAP). Intended to meet the needs of any possible reader, but specifically written to meet the needs of investigative sites and regulatory reviewers. Legally approved October 2018 Now that you have some idea of what the Common Protocol Template IS, let’s now consider what it IS NOT. The CPT is not a training document, nor is it a document for internal contracting of downstream activities within a Sponsor organization. The CPT is also not designed to be an enrollment feasibility document, nor a substitute for a Development Plan, Investigators’ Brochure or Statistical Analysis Plan (SAP). Finally, it is also very important to note that the CPT has not been created to meet the needs of any possible reader, but rather it is designed just for investigative sites and regulatory reviewers.

Thank you