Implementation Toolkit Executive Summary

1. Implementation Toolkit Executive Summary November 2018

2. TransCelerate: A Not-for-Profit Entity Created to Foster Collaboration • Our Shared Vision: • To improve the health of people around the world by accelerating and simplifying the research and development of innovative new therapies.

3. The Reach of our Global Membership is Expanding • Membership is available to biopharmaceutical research and development organizations that engage in innovative discovery, development and manufacturing of new medicines*. There are over 1,000 people from Member Companies that design and develop TransCelerate solutions. * to be eligible for membership, companies must meet specified eligibility criteria.

4. Why a Common Protocol Template? 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!” Heard at a June 2015 DIA meeting…

5. 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. • 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.

6. 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 • 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 • 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

7. Common Protocol Template is Intended to Prepare for the Future State Foundation Future Disclosure SAP CSR Human- Readable Protocol • 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 Machine- Readable Protocol Content Reuse IRB/IECs Sites Regulators Metadata driven processes eCRF Statistical Output

8. Current State/Future State: Establishing Our Direction • Today • Manual processes and interventions • Duplication of company efforts • Disconnected interfaces • Lot of customization • Long cycle times • Variable quality • High costs • Rework Where we should be… • Digital, Cloud-based, computable, re-usable • Patient-centric clinical trial design • Automated/seamless interfaces / parallel processing • Quality by design • Shorter cycle times • Cost efficient • “Integration of Data Analytics” Transformational Where we are… • Electronic, document based Incremental Where we started… • Paper-based, manual processing

9. How was the CPT Developed? Initial Advisory Committee Engagement FDA 18-Mar-2016:“Today we’re announcing a draft clinical trial protocol template developed by the Food and Drug Administration (FDA) and National Institutes of Health (NIH) that should help with that. …..We are aware of other efforts in this area, including one undertaken by TransCelerateBiopharma Inc. (TransCelerate), which has issued a common protocol template intended to be the basis for a forthcoming electronic protocol. Although our initial target audiences differ, we plan to collaborate with groups like TransCelerate to help ensure consistency for the medical product development community.” “…to inform the development of a common human readable and electronic protocol template and provide a forum for key stakeholders to inform future direction and provide know-how (Committee Charter)” eProtocol Advisory Committee “EMA has not agreed to take up a position on the Advisory Committee…..Happy to provide comments on any draft templates…” Other Advisors or Influencers

10. Alignment of CPT with NIH-FDA Template – May 2017 NIH-FDA Joint Protocol Team Rationale/Goal Mutual desire to harmonize CPT and NIH-FDA templates • Acknowledged different audiences: NIH-FDA template targeted at single-center and investigator led studies; CPT targeted at multi-center studies. • Harmonizing templates will drive harmonization in resulting protocols regardless of template used Both CPT and NIH-FDA templates to be maintained, modifications made to each to achieve greatest harmonization Updates Included Alignment on all Level 1 headings, and most Level 2 headings Revised order/placement of several sections • Where different Level 2 headings are required, they are placed after the common Level 2 headings. Combined several sections Harmonized terminology where applicable FDA Melissa Robb David Cho Owen Faris Peter Kim * Peter Marks Eileen Navarro-Almario * Vaishali Popat * Rachel Sherman NIH Michelle Culp Cynthia Boucher Christine Cutillo Daniel Falk Shanda Finnigan Adam Haim Barbara Karp Petra Kaufmann Lynette Nieman Sarah Read Megan Ryan Galia Siegel Steven Sparenborg Betty Tai AynurUnalp-Arida James Witter Anne Zajicek * Also on FDA’s CPT Working Group

11. Value Proposition – Why Should Sponsors Adopt? Quality • The expertise of 18+ sponsors has been tapped to develop the template with input from regulators, sites, CROs and an IRB – the work has been done for you. • The template includes TA –specific libraries based on sponsor best practices. • Stakeholders have the opportunity to suggest revisions; the template will be maintained and updated over time. • Broad adoption will help drive greater efficiency for investigators, sites, sponsors, and regulators. Efficiency • Sponsors can spend less time on low-value customization, and reduce time managing template maintenance. • The template is easy for authors to use. • Sponsors can adopt in a phased approach, and can choose to use either the Word version or Tech-Enabled version. You don’t have to go “all in” at the outset. Compliance • The template is supported by FDA, and Health Authority feedback to date has been unanimously positive. Quality + Efficiency + Compliance = Value Harmonization Value

12. Common Statistical Analysis Plan (SAP)Template - Benefits • Integration of templates • The Common SAP Template seamlessly integrates with the CPT and Common CSR simultaneously decreasing the overall complexity and variability between SAP template structures without limiting or dictating the type of analyses conducted resulting in increased ease of use and efficiency for sites and sponsors leading to downstream improvements in quality for patients. • Efficiency of authoring • The seamless content re-use and consistency in structure between CPT, Common SAP and Common CSR templates ensures that content can be efficiently authored with end uses clearly understood.

13. Common SAP Template – How was it developed? • Inputs: • Member Company SAP templates • Prior FDA feedback on CPT/Statistical Content and CPT version 2 (on which the FDA review was based) • Gamble C, Krishan A, Stocken D, et al. Guidelines for the Content of Statistical Analysis Plans in Clinical Trials. JAMA. 2017;318(23):2337–2343 • ICH E9 (R1) draft ‘addendum on estimands and sensitivity analysis in clinical trials to the guideline on statistical principles for clinical trials’  2017 • Process: • Author core content based upon review of Member Company templates and other documents • Developed a lean structure focusing on the needs of investigators and regulatory authorities • Incorporated estimands concept based upon draft ICH addendum • Review by extended TransCelerate member company representatives

14. Background: Why a Common Clinical Study Report (CSR)? • Problem Statement • Format and core content of study reports vary from sponsor to sponsor making review difficult for regulators • Study reports have become increasingly complex and lengthy driving up cost and time • Solutions • Develop a streamlined model clinical study report, including format and core content, to ease interpretation • Avoid redundancy • Enable downstream automation of many clinical processes like transparency and submission document authoring • Guiding Principles • Adherence with ICH E3 and CORE (Clarity and Openness in Reporting: E3-based) • “Common” in a CSR: 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 regulators are the first priority • A human readable template that paves the way for content reuse for transparency and submission document authoring

15. The Common CSR Potentially Benefits Many Stakeholders Near Term Potential Future State • Near Term Benefits to Sponsors • Reduction in redundant content • Improved way of working - writing lean CSRs with direct references to the protocol & SAP when applicable • Improved efficiency and reduced cycle time for the clinical study report and submission • Near Term Benefits to Regulators • Clinical Study Reports are lean (with direct references to the protocol & SAP when applicable, less duplication) • Aligned with ICH E3, CORE, EU CTR and PDUFA VI • Increased consistency between sponsors • Ease of review • Potential Future Benefits to Sponsors • Availability of machine readable CSR with Content Reuse capability • Automation of downstream processes and reuse of content for transparency • Potential Future Benefits to Regulators • Increased ease of data interpretation • Increased use of data standards enabling end-to-end use of metadata and traceability • Potential Future Benefits to Patients • Faster access to study results through reuse of content for transparency

16. Thank you