Why CPT? December 2017

Why a Common Protocol Template? “If you have standards without traceability, then you aren't really CDISC compliant.” Heard at a June 2015 DIA meeting… “Patient recruitment is challenged by the complexity of protocols. Sponsors do the same things too many different ways. Just make it the same!” FDA “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.” Legally approved 8-Apr-2017 Investigator Patient Advocate

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 8-Apr-2017 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.

End-User Stakeholders and Key “Must Haves” Define Scope and Solutions Investigators / Sites IRBs Physicians Clinical Scientists Operations Regulators Data Scientists Stats & Programming Metadata Traceability Reuse Automation Legally approved 8-Apr-2017 The CPT workstream is representative of end users, such as Clinical Development Scientists, Medical Writers, Data Scientists, and other professionals who develop protocols and implement clinical trials. The Team aims to evolve both a document-based protocol template as well as an early machine-readable protocol with the end users in mind. The blue arrow on the left side of the slide depicts the focus and makeup of people who typically comprise a sponsor’s study team while the red arrow on the right side of the slide reflects the focus of end users who are downstream of protocol development. The CPT endeavors to create connectivity from end to end. However, both document-based and digital solutions need to fit relatively seamlessly into the workflow of the Teams reflected on the left in order to drive uptake and minimize disruption. Metadata, Traceability, and automation of reuse have become the fulcrum upon which the CPT Team balances trade-offs in an effort to establish some level of harmonization in the way protocols are presented. Those elements which potentially limit the ability to create end-to-end traceability and automate reuse typically get more focus. Objectives Endpoints Methods Time & Events Supplies Protocol Representation Models (CDISC) Data Flows Data Standards Protocol Elements Concepts

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 8-Apr-2017 The benefit of the Common Protocol Template (CPT) will be felt by the separate and inter-related groups, as illustrated here.  The first step is the CPT will be used to create protocols supplied by the sponsor to the Investigators.  The Investigator and the site staff will see the common protocol structure in use, ideally by multiple sponsors, with same information in the same section across multiple sponsors.  The use of the CPT is expected to enable the site staff to more quickly develop their required study documents and tools by saving time looking for specific sections in a protocol document.  Protocols written using the CPT will be sent to the IRBs and Regulators.  The same effect is expected; the IRBs and Regulators will find the same information in the same location in protocols written using the CPT across multiple sponsors.  Use of this CPT, is expected to ease and facilitate the IRB review of protocols. The use of the CPT is projected to potentially shorten the start-up at the sites and the review by the IRBs and Regulators who will be reviewing information in the same structure across multiple sponsors. This may result in the study starting sooner, with a benefit to the patient who may be waiting to enter a clinical study. 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. Asthma and Diabetes available in the first release. 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 8-Apr-2017 Progress to date 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. The template consists of a core of common 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 - 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. inexperienced sites. A document for: internal contracting of downstream actions within the sponsoring organization. determining enrollment feasibility (specifically referring to the Synopsis section). An exposition of the Sponsor’s development program. A substitute for or duplicate of: Investigators’ Brochure. Statistical Analysis Plan (SAP). Intended to meet the needs of any possible reader, rather is specifically written to meet the needs of investigative sites and regulatory reviewers. Legally approved 8-Apr-2017

Thank you