Standard Analyses and Code Sharing (PhUSE Computational Science Working Group) CDISC Interchange 29 September 2016

Working Group Vision/Goals Leverage crowd-sourcing to improve the content and implementation of analyses for medical research, leading to better data interpretations and increased efficiency in the clinical drug development and review processes. Establish and maintain a publicly available repository for storing program code to be used as analytical tools for medical research. Where gaps exist, develop recommendations for analyses and displays in areas that could benefit from crowd-sourcing. Where gaps exist, develop code for recommended analyses and displays that could benefit from crowd-sourcing (to reside in the repository).

Vision: Fill the Gap on Analysis Standards Data Collection Systems Observed Datasets Analysis Datasets Tables, Figures and Listings Clinical Data Flow Trial Design PRM SDTM ADaM No TFL Stds Exist Industry Standards Alignment CDASH A lot of progress has been made with respect to standardization – mostly in the collection and data space. There’s a gap with respect to analyses and displays. CFAST = Coalition for Accelerating Standards and Therapies CFAST (Therapeutic Areas)

Vision: Shared Reusable Code Library (Script Repository) Can be a place to share code for ADaM derivations Repository: Standard Qualified Scripts Industry FDA Academia Vision of the Script Repository – Reusable code library – Utilizing crowd-sourcing to maintain. All inclusive. Assumes SDTM/ADaM data structure. Currently SAS and R focus but not intended to be limited to those. Getting code associated with the white papers is a current focus. Adding some standard code that FDA medical reviewers use is also a focus. SAS Cloud R Studio Whitepaper Scripts Contributed Scripts

Three Focus Areas, 5 active projects Script Repository (3 projects) Script Discovery and Acquisition (SDA, Rebeka Revis, Michael Man) Repository Content and Delivery (RCD, Gustav Bernard, Andrew Miskell) Repository Governance and Infrastructure (RGI, Mike Carniello, Hanming Tu) Analyses and Display White Papers (ADW, Mary Nilsson) Communication, Promotion, Education (CPE, Jared Slain and Wendy Dobson)

New Project – Test Dataset Factory Background: Several PhUSE projects develop scripts/concepts that need to be tested with trial datasets Use of CDISC pilot datasets and/or datasets from team members for testing isn’t sufficient in many cases Approach and Objective: Determine test dataset requirements (like # of subjects, observation parameters, etc.) Implement scripts that create ‘simulated’ SDTM and/or ADaM data sets Publish datasets and if possible user-configurable scripts Team: Project co-lead: Peter Schaefer (pschaefer@vca-plus.com) Status: Completed a proof of concept Working on scope specification and priorities Need to recruit team members to move ahead CDISC participation would be appreciated! Want to use R as the scripting language, this would enable us to easily host the scripts in a cloud-based environment

New Project Idea – Best Practices on Data Collection Instructions Adverse events, concomitant medications, study disposition, reasons for permanent discontinuation from study treatment Will potentially lead to increased efficiency (site personnel won’t have to learn as many collection methods) and fewer queries (less confusion by site personnel), Will enable more standardization in data, analyses, displays For some data domains (e.g., adverse events, concomitant medications, study disposition, reasons for permanent discontinuation from study treatment), sharing best practices on collection instructions will potentially lead to increased efficiency (site personnel won’t have to learn as many collection methods) and fewer queries (less confusion by site personnel), and will enable more standardization in analyses and displays for data common across therapeutic areas.  Unnecessary variations in collection instructions are creating inefficiencies and limiting abilities to fully leverage data standards.  Collection and associated instructions may vary depending on whether the study is early- versus late-stage (as discussed in the February 2016 FDA guidance “Determining the Extent of Safety Data Collection Needed in Late-Stage Premarket and Postapproval Clinical Investigations”), however, reducing the extent of variation would be beneficial for medical research.    Potential impact on SDTM/ADaM

Working Group Accomplishments 5 White Papers finalized Vital Signs, ECGs, Labs - Central Tendency Finalized in October 2013, Lead – Mary Nilsson Non-Compartmental Pharmacokinetics Finalized in March 2014, Lead - Francois Vandenhende Demographics, Disposition, and Medications Finalized October 2014, Lead – Simin Baygani Vital Signs, ECGs, Labs – Outliers and Shifts Finalized in September 2015, Lead – Wei Wang QT Studies Finalized in March 2016, Lead – Christos Stylianou How to find final white papers: Go to www.phuse.eu, Click on CS Working Groups, Click on CS Deliverables Catalog

Working Group Accomplishments AE White Paper out for public review This is the 2nd and last draft Comments due 14 October 2016 Expected to be final by end of 2016 Lead – Sheryl Treichel, Nhi Beasley, Mary Nilsson http://www.phuse.eu/cs-deliverables-under-review.aspx Upcoming white papers for public review Hepatotoxicity Working on Draft 1 for public review Should be ready approximately October Lead – Terry Walsh Please review and recruit reviewers!

Working Group Accomplishments Script Repository has been created Started in Google Code, now in GitHub MIT license chosen Process guidelines developed Qualification guidelines developed User-friendly front end developed https://github.com/phuse-org/phuse-scripts http://www.phusewiki.org/wiki/index.php?title=User_Guide_for_Standard_Script_Repository

Working Group Accomplishments Scripts exist in the repository Several scripts at various stages (5 Script-athons, plus additional work by the project team) Focused on creating scripts associated with the displays in the white papers, starting with ADaM data The specifications for the scripts include assumptions and required ADaM variables Starting with CDISC pilot data Received scripts that are part of FDA’s JumpStart service A couple last year, additional scripts this year

Working Group Needs More project team members Increased participation in white paper reviews – Help recruit! Use/reference recommendations in existing final white papers! Forward to any existing standards groups Link to white papers from Statistical Analysis Plans Participate in re-usable code development Write, Test, Qualify, Review, Improve Keep eyes open for existing scripts that need a public home Advertise! Advertise! Advertise!

How to Participate Sign up for the PhUSE working group mailings From phusewiki.org, click “Join a Working Group Now” Standard Scripts Groups CSS-WG-Standard-Scripts (Entire Working Group) CSS-WG-Standard-Scripts-WhitePapers (White Paper Project Team) CSS-WG-Standard-Scripts-Platform (Script Repository) CSS-WG-SS-WhitePaperReviewers (Notified when a white paper is ready for review) See wiki pages for each of the projects (www.phusewiki.org)