Common Protocol Template (CPT) Release 3 Highlights May-2016

Table of Contents Section Slide(s) Summary of CPT Releases 3 Installation Instructions for Release 3 4 Primary Features of the Tech-Enabled Edition 5-10 Release 3 - Functionality Updates to Tech-Enabled Edition 11-20 Release 3 - Amendment Process 21 Release 3 - Content Updates 22-37

Summary of CPT Releases Intended Audience Template editions included Release Number Release Date Member Companies Public Basic Word Tech-Enabled 1.0 Aug-2015  2.0 Dec-2015 3.0 June-2016 4.0 Planned 4Q2016

Installation Instructions for Release 3 For new users (no prior CPT edition installed) Please follow the CPT Installation Instructions document. http://www.transceleratebiopharmainc.com/assets/common-protocol-template/ For users updating to Release 3 (prior CPT edition already installed) Please uninstall the previous version and then follow the CPT Installation Instructions document. Go to Control Panel>Programs and Features> and select the below 2 files to uninstall: CPT Intelligent Content Management CPT Library Management Add-In

Basic Features of the Tech-Enabled Edition Architectural Approach To provide a single template applicable to all study phases and types, the CPT has been created using a modular approach to manage information. The Core Backbone establishes a common heading structure and recommended content applicable to all protocols, while content specific to participant type or disease area are separated into libraries. To facilitate the user experience, manage the diverse information components, and enable reuse of content, the automated CPT was created within the MSWord environment via customized Add-ins. Utilization of a metadata driven XML framework further facilitates content reuse and establishes the foundation for traceability and automation

Basic Features of the Tech-Enabled Edition Navigation Pane By enabling the navigation pane in the “View” tab of Word, the user will be able to see an interactive TOC within the CPT that will allow easy navigation throughout the sections of the template. Data Sources Pane The Data Sources Pane aids the user in managing the various library content and related instructional information supporting the template: a. Filter Library List Box Panel b. Instructional Text Box Panel c. Library Content Tree View Panel d. Preview Text Box Panel

Basic Features of the Tech-Enabled Edition Libraries These Libraries are currently available in CPT: Asthma Diabetes Healthy Volunteer Patient Configuring the libraries is done through the Data Sources Pane:

Basic Features of the Tech-Enabled Edition CPT Tab The CPT Tab within Word appears upon installations of the customized CPT add-ins. Users should navigate to this tab in order to utilize the customized features created to manage CPT content. Examples include a variables list of content controls for common protocol elements, utilities to facilitate removal of example text, access to useful links, and a button for activating/deactivating the instructional text display. Detailed description of all the Technology-enable CPT functionality is found in the CPT Guidance for Use V2.

Basic Features of the Tech-Enabled Edition Content Controls The use of content controls imbedded within the CPT and associated libraries enables the building of the XML backbone when drafting a protocol and facilitates content reuse in other parts of the document or potentially in other documents. Users can enter their own data into a content control or insert from a Library. Content Controls were also used to create a common variables list that allows the author to insert a control in multiple locations (for example – “Protocol Number”) and if an edit is made to one instance, it will be reflected in all other locations of the variable. Below, the protocol number was established on the title page and updated as well in the document header which also contains the content control for that variable.

Basic Features of the Tech-Enabled Edition XML Extracts Users are able to extract the data that’s entered in the protocol through the export functionality built into the template. A user would export the protocol and view data as illustrated below:

Release 3 - Functionality Updates to the Tech-Enabled Edition The Following features are new or enhancements to the CPT for Release 3: Prerequisite Analyzer CPT Tab Example Text Tools Useful Links Button About Button CPT Admin Tab Managed Variables Button Import/Export Buttons Objectives and Endpoints Table Section 1 - Synopsis Table Section 4 – Objectives and Endpoints Table

Prerequisite Analyzer The prerequisite analyzer will scan a user’s PC and confirm the appropriate versions of required programs have been installed.

CPT Tab – “Example Text Tools” In the Example Text Tools subsection of the CPT menu, we have 3 buttons, Convert, Remove and Next. (1) Convert – Converts example text to regular text. Contains a drop down menu that allows users to covert 1 instance of example text and move to the next or to convert ALL example text in the document

CPT Tab – “Example Text Tools” cont. (2) Remove – Removes example text from document. Contains a drop down menu that allows users to remove1 instance of example text and move to the next or to remove ALL example text in the document (3) Next - Searches for the next instance of example text in the document

CPT Tab – “Useful Links” Useful Links Button The “Useful Links” button will contain links to the TransCelerate website that will contain helpful information to the users about the template Currently we have two links set CPT Feedback – Links to the CPT Feedback form on the TransCelerate site CPT User Resources – Links to the FAQs & other supporting documentation on the CPT on the TransCelerate site

CPT Tab – “About” The “About” button will show Version information and a link to the log files for the CPT Add-Ins A new section entitled “Manage Templates” to help facilitate installing and updating A new section entitled “Advanced Settings” to control access to administrative features

CPT Admin Tab This tab maintains functions specifically targeted for administrative/technical users.* Manage Variables Button - will allow users to edit and manage variables in the template Export/Import Data - will allow users to import and export the XML of the created variables in the template and have the ability to feed into another system * Administrative/technical users would be those familiar with content management functions within word, content re-use with downstream documents, etc.(e.g. template managers)

Objective and Endpoint Table Updates Section 1 - Synopsis Table This section is “read only” and upon first opening the synopsis section, it will be unpopulated. The objective/endpoints table will become populated after objectives and endpoints are entered first in Section 4 of the template.

Objective and Endpoint Table Updates Section 4 – Objectives and Endpoints Table With this release, a new row is required for each new objective. Multiple endpoints per objective can be added inside of a cell in the table and will be visually aligned.

Objective and Endpoint Table Updates Updating Section 1 – Synopsis The Synopsis table will be updated after the Objectives and Endpoints table in Section 4.0 is populated. The author exits the Section 4.0 table and selects the objectives/endpoints to include, then clicks the refresh button. By default all primary objectives are selected and the user may select the key secondary objectives to include.

Release 3 - Amendment Process Protocol amendments are created by saving the current protocol version as a new document, and making the amendment changes directly within the new document (amendment). The templated PROTOCOL AMENDMENTS SUMMARY OF CHANGES TABLE section and its instructions are copied from the Common Protocol Template and pasted into the amendment document directly before the Table of Contents. The section includes: A DOCUMENT HISTORY containing the Document Number and Date of Issue for each amendment. Overall Rationale for the Amendment Description of Changes/Rationale

Release 3 – Selected Content Updates Core Backbone Healthy Volunteer Library Patient Library Asthma Library Diabetes Library Selected Content Updates are presented in the following tables. Users of the CPT should review the Release 3 templates and comparison documents carefully for awareness of detailed changes included.

Core Backbone – Selected Template Changes in Release 3 Release 3 Section # and Name Description of Change from Release 2 Brief Rationale Title Page “Short Title” added To provide a shorter version of the title (maximum 300 characters) that may be used for Registry databases. Protocol Amendment Summary of Changes Table New Section added. To provide a summary of all changes included in the Protocol amendment as compared to the prior protocol/amendment

Core Backbone – Selected Template Changes in Release 3 Release 3 Section # and Name Description of Change from Release 2 Brief Rationale 5.3 Participant and Study Completion Change in Section heading - changed from “ End of Study Definition”, Text added to clarify the meaning of study completion. To provide definitions for participant completion of study, as well as study completion aligned with Registry database definitions. 5.5 Dose Justification Change in Section heading - changed from “Justification for Dose” To reflect input from template reviewers to provide alignment with “Dose Modification” heading.

Core Backbone – Selected Template Changes in Release 3 Release 3 Section # and Name Description of Change from Release 2 Brief Rationale 6.1 Inclusion Criteria New criterion added for Age. Instructions added regarding criteria around rescreening and body weight. To provide additional detail regarding authoring of this criterion. 7.2 Dose Modification Change in Section location – previously was Section 7.4 To reflect input from template reviewers to provide improved flow of information. 7.3 Method of Treatment Assignment Change in Section location – previously was Section 7.2

Core Backbone – Selected Template Changes in Release 3 Release 3 Section # and Name Description of Change from Release 2 Brief Rationale 7.4 Blinding Change in Section location – previously was Section 7.3 To reflect input from template reviewers to provide improved flow of information. 7.7.1 Rescue Medication New Section heading added. To facilitate easier location of information regarding rescue medication. 8. Discontinuation/ Withdrawal Criteria Change in Section heading – changed from “Discontinuation Criteria” To better reflect the content of the section.

Core Backbone – Selected Template Changes in Release 3 Release 3 Section # and Name Description of Change from Release 2 Brief Rationale 8.1.2 Re-challenge Change in Section heading – changed from “Rechallenge” To reflect input from template reviewers. 8.2 Withdrawal from the Study Change in Section heading – changed from “Discontinuation from the Study” To better differentiate between participant discontinuing the study treatment and withdrawing from the study. 9.2.1 Time Period and Frequency for Collecting AE and SAE Information Text revised. To allow for the possibility of different reporting time frames to be defined for AEs vs SAEs.

Core Backbone – Selected Template Changes in Release 3 Release 3 Section # and Name Description of Change from Release 2 Brief Rationale 9.2.5 Cardiovascular and Death Events New Section added. To facilitate easier location of information regarding these event types. 9.2.6 Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs or SAEs To provide a section to describe events that are typically associated with the disease under study and will not follow the standard reporting process for AE/SAEs. 9.2.7 Pregnancy Change in Section location – previously was Section 9.2.5 To reflect input from template reviewers to provide improved flow of information.

Core Backbone – Selected Template Changes in Release 3 Release 3 Section # and Name Description of Change from Release 2 Brief Rationale 9.2.8 Medical Device Incidents (Including Malfunctions) Change in Section location – previously was Section 9.2.6 To reflect input from template reviewers to provide improved flow of information. 9.4 Safety Assessments Change in Section heading – changed from “Safety” To reflect input from template reviewers to provide alignment with “Efficacy Assessments” heading. 9.7 Genetics Change in Section heading – changed from “[Pharmacogenomics] or [Genetics]” To reflect input from template reviewers.

Core Backbone – Selected Template Changes in Release 3 Release 3 Section # and Name Description of Change from Release 2 Brief Rationale 9.8 Biomarkers [and Imaging] Change in Section heading – changed from “[Biomarkers]” To provide clarity that this section may also include information about Imaging procedures. 9.8.1 Immunogenicity Assessments [If applicable] Suggested Text removed from template. To reflect input from template reviewers. 9.8.2 RNA Transcriptome Research [If applicable]

Core Backbone – Selected Template Changes in Release 3 Release 3 Section # and Name Description of Change from Release 2 Brief Rationale 9.8.3 RNA Expression Research of a Subset of RNA Species [If applicable] Suggested Text removed from template. To reflect input from template reviewers. 9.8.4 Proteome Research [If applicable] 9.8.5 Metabolome Research [If applicable] Change in Section heading – changed from “Metabolomic Research [If applicable].” Suggested Text removed from template.

Core Backbone – Selected Template Changes in Release 3 Release 3 Section # and Name Description of Change from Release 2 Brief Rationale 9.9 [Health Economics] OR [Medical Research Utilization and Health Economics] Change in Section heading – changed from “Health Economics OR Medical Research Utilization and Health Economics” To reflect input from template reviewers to allow flexibility in the title of this section to align with the content included. Appendices Appendices are no longer subsections of Section 12. Instruction added to confirm that appendices may be modified, deleted or added as needed To reflect input for template reviewers to list appendices as separate from the body by removing section numbers, and to provide clarity in instructions for appendices.

Core Backbone – Selected Template Changes in Release 3 Release 3 Section # and Name Description of Change from Release 2 Brief Rationale Appendix 3: Study Governance Considerations Common Text added regarding “Study and Site Closure.” To provide additional detail regarding authoring of this content. Appendix 5: Contraceptive Guidance and Collection of Pregnancy Information Subsection headings no longer appear in Table of Contents. Note: Appendix 5 content was previously updated to align with CTFG (Clinical Trials Facilitation Group) guidance as part of Release 2. To provide a consistent and streamlined approach to Table of Contents elements, limited only to Appendix titles.

Core Backbone – Selected Template Changes in Release 3 Release 3 Section # and Name Description of Change from Release 2 Brief Rationale Appendix 6: Genetics Change in Appendix title – changed from “Pharmacogenomics” To align with update in related “Genetics” section heading. Appendix 7: Liver Safety: Suggested Actions and Follow-up Assessments [and Study Treatment Rechallenge Guidelines] Change in Appendix title – changed from “Liver Safety: Suggested Actions and Follow-up Assessments AND Study Treatment Rechallenge Guidelines” To correct an inconsistency between the section heading and Table of Contents reference, and to allow for flexibility in the title of this section to align with content included.

Core Backbone – Selected Template Changes in Release 3 Release 3 Section # and Name Description of Change from Release 2 Brief Rationale Appendix 10: Protocol Amendment History New Appendix added. To align with the Protocol Amendment Summary of Changes Table in the beginning of document and to provide location for information pertaining to previous amendments.

Healthy Volunteer Library – Selected Template Changes in Release 3 Release 3 Section # and Name Description of Change from Release 2 Brief Rationale 6.2 Exclusion Criteria Updates made to several criteria. To reflect input from template reviewers. Appendix 7: Liver Safety: Suggested Actions and Follow-up Assessments [and Study Treatment Rechallenge Guidelines] Update made to Follow-Up Assessments

Patient Library – Selected Template Changes in Release 3 Release 3 Section # and Name Description of Change from Release 2 Brief Rationale 6.2 Exclusion Criteria Updates made to several criteria. To reflect input from template reviewers. Appendix 7: Liver Safety: Suggested Actions and Follow-up Assessments [and Study Treatment Rechallenge Guidelines] Update made to Follow-Up Assessments

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