Demystifying Interpretation of Guidances Regulations August 2020 For

Demystifying Interpretation of Guidances & Regulations August 2020 For member company use only

INTERPRETATION OF GUIDANCES AND REGULATIONS What is IGR? How are IGR Topics selected? How are IGR Topics run? How can IGR deliverables be leveraged? What questions and suggestions do you have to enhance the value of IGR? Copyright © 2020 Trans. Celerate Bio. Pharma Inc. , All rights reserved. * Confidential - NOT FOR DISTRIBUTION * 2

What is “IGR”

Interpretation of Guidance & Regulations Overview UNMET NEED Historically, there have been challenges addressing ambiguous regulations/ guidances and Health Authority operational expectations. Specific challenges have included one or more of the following elements: • Substantive ambiguities in text of regulation/guidance, which may result in, among other things, challenges in interpreting regulations/guidances • Divergence in regulatory requirements and expectations across global Health Authorities • Real world impediments to operationalizing Health Authority expectations PROJECT DESCRIPTION This initiative will share expertise to more efficiently and effectively meet the intent of ambiguous regulations/ guidances and Health Authority operational expectations around the world. Secondarily, the initiative will take opportunities to raise Health Authority awareness of the real life impact of ambiguous regulations/ guidelines. While addressing these aims, the initiative will consider the highest priority to be continued enhancement of patient safety. VALUE Addressing these challenges will bring value to patients, sponsors, and regulators. Examples of value include: • • Enhanced patient outcomes/safety through a better understanding and exploration of operational best practices to meet ambiguous regulations/ guidances Reduced sponsor inspection and compliance risks through better understanding of regulations/ guidances Increased effectiveness and efficiencies in meeting the operational expectations of ambiguous regulations/ guidances Clarification of ambiguous regulations/ guidances through proactive sharing of feedback, observations, consequences, and proposed best practices with Health Authorities Copyright © 2020 Trans. Celerate Bio. Pharma Inc. , All rights reserved. * Confidential - NOT FOR DISTRIBUTION * 4

Interpretations of Guidances & Regulations Roadmap 2017 • Kicked-off IGR workstream • Kicked-off first 2 PV Topics 2018 • Added 2 additional PV Topics • Completed 1 PV Topic 2019 • Expansion to Clinical Guidances & Regulations, kicking off 1 Clinical Topic 2020 & Beyond • Continue Copyright © 2020 Trans. Celerate Bio. Pharma Inc. , All rights reserved. * Confidential - NOT FOR DISTRIBUTION * 5

What is similar and different from other workstreams? Similarities Differences IGR has a similar structure New topics are selected throughout the year Sponsors – Clinical: Simon Trowel (GSK) PV: Sabine Jeck-Thole (BI) A “type” of Core Team Dedicated SMEs IGR is really 2 workstreams (PV and Clinical) Leverages the PMO and Program Leads Has same innovative goals Copyright © 2020 Trans. Celerate Bio. Pharma Inc. , All rights reserved. While IGR has a similar structure, its “topics” run as mini-workstreams, each with their own with deliverables Topics are typically very independent of each other While not a SPRINT, that model is a basis for running the topics IGR does not currently have an end date * Confidential - NOT FOR DISTRIBUTION * 6

Interpretation of Guidances & Regulations Workstreams Organization IGR - PV Copyright © 2020 Trans. Celerate Bio. Pharma Inc. , All rights reserved. IGR - Clinical * Confidential - NOT FOR DISTRIBUTION *

Interpretation of Guidances & Regulations Workstreams PV Core Team Members Name Company Melissa Truffa Abb. Vie Janis Little Allergan Joe Viscosi Allergan Michelle Geller Amgen Ken Twomey Astrazeneca Krisztina Debreczeni BMS Sabine Jeck-Thole Boehringer Ingelheim Ajay Singh GSK Kelly Benner Janssen Sadiqa Mian Lilly Nina Stuccio Merck Julia Appelskog Merck KGa. A David Lewis Novartis Gary Wilson Pfizer Cuancha-Maria Manning Regeneron Maritess Esguerra Roche Anne Dal. Pra Sanofi Shalini Patel UCB Copyright © 2020 Trans. Celerate Bio. Pharma Inc. , All rights reserved. * Confidential - NOT FOR DISTRIBUTION * 8

How are IGR Topics selected

Framework For Selecting Topics Overview • PV will make their selection using the IGR PV Core Team • Clinical will leverage an ILT discussion 01 Create Short List 02 Prioritize 03 Discuss / Confirm • When a topic completes, a slot opens for a new topic • Committee will develop a “short list” of key guidances • These are discussed and a selection is made typically based on level of interest and commitment to resource Copyright © 2020 Trans. Celerate Bio. Pharma Inc. , All rights reserved. 04 Initial Resourcing * Confidential - NOT FOR DISTRIBUTION *

Resourcing Approach for IGR Teams 1. When the topic is selected, the input during the selection process is leveraged to identify a potential lead 04 Initial Resourcing 2. Leads are interviewed and a selection is made 3. The lead helps to develop team resource descriptions. A specific set of information is requested on each nominee: • For PV – this is initially sourced through the IGR PV Core Team. If needed, we will reach farther into the MC network • For Clinical – Resources are posted 4. Nominations are reviewed by the Lead and Sponsor 5. The team is selected 6. For Clinical, a “Stakeholder” or “ Reference” Team has been created to allow additional MCs to participate. Copyright © 2020 Trans. Celerate Bio. Pharma Inc. , All rights reserved. * Confidential - NOT FOR DISTRIBUTION *

IGR: Quality Tolerance Limits Topic Resourcing makes all the difference! Team Kick-off F 2 F #1 Apr 2019 May 2019 F 2 F #2 External Comment Deliverables Shared Externally Jul 2019 Sep 2019 Nov 2019 Q 2 2020 Right Resources on Team • Team make-up includes a variety of experience and expertise • • Strong Lead ILT resourced quickly Small and agile team QTL Stakeholder Team as a balance between MC involvement and the need for a small team Copyright © 2020 Trans. Celerate Bio. Pharma Inc. , All rights reserved. Focused Effort by Team • Week-long F 2 F allowed team to make significant progress on deliverables in a short period of time • Dedicated time by the team * Confidential - NOT FOR DISTRIBUTION *

How are IGR Topics run

Interpretation of Guidance & Regulations Framework For Running Topics Month 1 Month 2 Month 6 Month 3 -5 Core Team/Legal Project Description Checkpoint 01 Resource Team 02 Project Description 03 Methodology /Timelines Stakeholder Engagement Plan Core Team/Legal/Advisory Team Checkpoints T Copyright © 2020 Trans. Celerate Bio. Pharma Inc. , All rights reserved. Realize Checkpoint 04 05 Interpret and Develop Deliverables Leverage Templates 06 Reflect /Realize/ Celebrate Checkpoint * Confidential - NOT FOR DISTRIBUTION *

Interpretation of Guidance & Regulations Develop Project Description Copyright © 2020 Trans. Celerate Bio. Pharma Inc. , All rights reserved. 15

How can IGR deliverables be leveraged

Interpretation of Guidance & Regulations Current Regulations & Guidances The initiative has or is addressing the following ambiguous PV regulations and guidances Draft Guidance for Industry Safety Assessment for IND Safety Reporting CTFG Q&A document – Reference Safety Information (Draft Guidance Issue Date Dec 2015) (Q&A Issue Date Nov 2017) Complete Interpret ambiguous portions of draft guidance, engage with regulators, and share findings on implementation challenges and approaches Interpret ambiguous portions of RSI Guidance Q&A; engage with regulators, share findings on implementation challenges, approaches, and regulator feedback Copyright © 2020 Trans. Celerate Bio. Pharma Inc. , All rights reserved. PMSR for Combination Products Draft Guidance for Industry and FDA Staff (Draft Guidance Issue Date Mar 2018) Safety Issue Notification Guidances/ Regulations (Australia, Canada, Israel, New Zealand, Saudi Arabia, Switzerland, Turkey) IND Safety Reporting to FAERS (Draft Guidances Issue Date Oct 2019) Complete Enhance patient safety by facilitating adherence to unclear regulatory guidance calling for applicants to take a more holistic view of combination products Support patient safety commitments by identifying various approaches to meet Health Authority expectations for safety issue notifications in an effective and efficient manner Provide a consolidated set of Trans. Celerate Member Company comments to FDA specific to the draft guidances on IND Safety Reporting to FAERS Presentation of Risks During Clinical Development and Immediately Postapproval Ongoing Interpret ambiguous portions of guidances related to the categorization of risks in clinical development and share findings on implementation challenges and approaches * Confidential - NOT FOR DISTRIBUTION * 17

Interpretation of Guidance & Regulations Current Regulations & Guidances The initiative has or is addressing the following ambiguous Clinical regulations and guidances ICH E 6(R 2): Quality Tolerance Limits (Nov 2016) Copyright © 2020 Trans. Celerate Bio. Pharma Inc. , All rights reserved. General Data Protection Regulation: Data Reuse Assets available Ongoing Improve the systematic quality of Clinical Research through the implementation of QTLs in a way that facilitates compliance, efficiency and minimizes confusion and duplication of effort Develop a GDPR Clinical Data Reuse Framework which includes: Principles for responsible data reuse Develop a Unified Data Protection Methodology specific for Trans. Celerate Data. Celerate (e. g. , Placebo Standard of Care) * Confidential - NOT FOR DISTRIBUTION * 18

Interpretation of Guidance & Regulations Types of deliverables Socialization Materials Deliverables Example socialization approaches Implementation Toolkits • Interpretation • Implementation considerations • Process flow charts • Examples • Definitions Publications • Journal article • White papers • Materials on Trans. Celerate website Copyright © 2020 Trans. Celerate Bio. Pharma Inc. , All rights reserved. Supportive Materials • Infographic • Templates • FAQs External Engagements • Health Authority influence • Industry organizations • CRO Forum • Sites (eg, survey) External Tools • Program leads update • Topic and reference team distribution • Conference presentations • Webinars • Posters 19 * Confidential - NOT FOR DISTRIBUTION *

Interpretation of Guidances & Regulations - PV IND Safety Reporting Description Guidance/Regulation Draft Guidance for Industry Safety Assessment for IND Safety Reporting (Dec 2015) AGENCY FDA GUIDANCE DATE December 2015 APPROACH 1. Reviewed 2015 Draft Guidance and identified areas that may need clarification 2. Conducted Member Company surveys to examine how companies interpreted recommendations in the 2015 Draft Guidance Deliverables MANUSCRIPT Industry Experience and Perspective on Clinical Trial Safety Reporting to the FDA (Available soon on Trans. Celerate website) 3. Shared findings with FDA VALUE Understanding current approaches of Sponsors to Clinical Trial Safety Monitoring and Reporting and interpretation of Draft 2015 IND Guidance. Copyright © 2020 Trans. Celerate Bio. Pharma Inc. , All rights reserved. * Confidential - NOT FOR DISTRIBUTION *

Interpretation of Guidances & Regulations - PV Reference Safety Information Description Guidance/Regulation CTFG Q&A document – Reference Safety Information (Nov 2017) AGENCY EMA GUIDANCE DATE November 2017 APPROACH 1. Review 2017 CTFG Q&A regarding RSI and identify areas needing clarification 2. Conduct Member Company survey to see how they implemented the new RSI guidelines in context of other global regulations VALUE • Raises industry and Health Authority awareness of diverging regulations/guidances through sharing key points in publications and conferences • Provides visibility into how sponsors are meeting the requirements for RSI Copyright © 2020 Trans. Celerate Bio. Pharma Inc. , All rights reserved. Deliverables MANUSCRIPT Examines how pharmaceutical companies are operationalizing the CTFG Q&A guidance on RSI and managing compliance with non-harmonized worldwide regulatory requirements. (Available soon on Trans. Celerate website) CALL FOR RE-HARMONIZATION A letter to the editor of Clinical Trials, noting a trend towards divergence of pharmacovigilance regulations. This letter is a call for re-harmonization to raise awareness of the issue and call for all stakeholders, in particular Health Authorities, to take efforts to re-harmonize. (Link to Letter to the Editor) * Confidential - NOT FOR DISTRIBUTION *

Interpretation of Guidances & Regulations - PV Postmarketing Safety Reporting for Combination Products Description Guidance/Regulation Postmarketing Safety Reporting for Combination Products Draft Guidance for Industry & FDA Staff AGENCY FDA GUIDANCE DATE March 2018 APPROACH 1. Reviewed Draft Guidance 2. Identified ambiguous areas to interpret and shared best practices through the implementation guide 3. Conducted industry-wide webinars sharing the implementation guide VALUE Facilitating adherence to unclear regulatory guidance calling for applicants to take a more holistic view of combination products to enhance patient safety. Copyright © 2020 Trans. Celerate Bio. Pharma Inc. , All rights reserved. Deliverables IMPLEMENTATION GUIDE An Implementation Guide to aide pharmaceutical manufacturers‘ understanding of ambiguous areas of the PMSR for Combination Products Draft Guidance for Industry and FDA Staff (March 2018). (Link to Implementation Guide) WEBINAR A webinar presentation where Trans. Celerate team members provide an overview of the FDA Post Marketing Safety Reporting for Drug-Device Combinations Implementation Guide. (Link to Webinar) * Confidential - NOT FOR DISTRIBUTION *

Interpretation of Guidances & Regulations - PV Safety Issue Notification Guidances & Regulations Description Guidance/Regulation APPROACH 1. Reviewed applicable country guidances and proposed reference definitions 2. Gathered MAH insights 3. Compiled findings and proposals into an implementation guide VALUE Supports patient safety commitments by identifying various approaches to meet Health Authority expectations for safety issue notifications in an effective and efficient manner Copyright © 2020 Trans. Celerate Bio. Pharma Inc. , All rights reserved. Deliverables SAFETY ISSUE NOTIFICATION GUIDE A guide to aide understanding of safety issue notification guidances and regulations for in-scope countries. (Link) WEBINAR A webinar presentation where Trans. Celerate team members provide an overview of the Safety Issue Notification Guide (Link) * Confidential - NOT FOR DISTRIBUTION *

Interpretation of Guidances & Regulations - Clinical Quality Tolerance Limits Description Guidance/Regulation Integrated Addendum to ICH E 6(R 1): Guideline for Good Clinical Practice E 6(R 2) AGENCY: ICH GUIDANCE DATE: November 2016 APPROACH 1. Review 2016 Guidance and identify areas that may need clarification 2. Provide greater clarity on how to interpret and operationalize QTLs as per ICH E 6 R 2 through deliverables VALUE Improve the systematic quality of Clinical Research through the implementation of QTLs in a way that facilitates compliance, efficiency and minimizes confusion and duplication of effort Copyright © 2020 Trans. Celerate Bio. Pharma Inc. , All rights reserved. Deliverables CPT & CSR TEXT Proposed model instructional text for inclusion in the Trans. Celerate CPT and CSR Templates (Available in Dec CPT/CSR Release) QTL FRAMEWORK & FAQs A framework including proposed definition of a QTL, process map/steps & examples of QTL parameters (Available through Program Leads) QTL Plan Template A study level template sponsors can leverage to define and monitor QTLs (Available through Program Leads) MANUSCRIPT(S) Peer-reviewed publication which will share work done for the definition and parameter guides. A second publication is under consideration which would share and speak to QTL historical data. (Not yet available) * Confidential - NOT FOR DISTRIBUTION *