Systematic Risk Management: An Overview of ICH Q-9

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1 Systematic Risk Management: An Overview of ICH Q-9 March 12, ParagonRx International LLC

2 Today s Session Systematic Risk Management: An Overview of ICH Q-9 Speakers: Jeff Fetterman, President, ParagonRx Stephen Sun, MD, MPH, Chief Medical Officer, ParagonRx 2

3 Overview of Topics Growing regulatory imperative for systematic and standardized risk management methods FDA/ICH Q-9 Guidance on Quality Risk Management What Q-9 offers risk management professionals How to get started and communicate these methods to business executives 3

comprehensive strategy to ensure all risks have been

significant FDA s Benefit-Risk Framework Systematic

of review staff throughout the lifecycle of a drug

Mitigation Strategies (REMS) Through Systematic Analysis,

4 Growing Regulatory Imperative for Systematic and Standardized Methods -- FDA Systematic approach is a comprehensive strategy to ensure all risks have been considered since the consequences of failure can be significant FDA s Benefit-Risk Framework Systematic approach to benefit-risk assessment should support the work of review staff throughout the lifecycle of a drug Brookings Institute REMS: Strengthening Risk Evaluation and Mitigation Strategies (REMS) Through Systematic Analysis, Standardized Design, and Evidence-Based Assessment FDA and EMA Strengthen Collaborate in PV Feb. 19, 2014 The PV cluster will provide a forum for a more systematic and focused exchange of information on the safety of medicines. 4

Risk-Based Monitoring for Clinical Studies Demand a Structured Systematic

Building Quality-by-Design into trials 2. Early and ongoing risk assessment 3.

accept less than 100% source data verification and source data review if. 4.

5 Risk-Based Monitoring for Clinical Studies Demand a Structured Systematic Risk Assessment MUST MAINTAIN: Subject Safety Data Quality 1. Building Quality-by-Design into trials 2. Early and ongoing risk assessment 3. Focus on Critical Processes and Critical Data Regulators are willing to accept less than 100% source data verification and source data review if. 4. Use of Risk Indicators and Thresholds 5. Adjust Monitoring Activities Based on the Issues and Risks 5

6 EMA s Reflection Paper on Risk-Based Quality Management in Clinical Trials Well established methods, like fishbone diagrams or Failure Mode and Effects Analysis (FMEA), take into account likelihood of occurrence, impact, and detectability of risks and can be useful tools. The establishment of priorities will contribute to the identification of the risks that need to be mitigated and which should be the object of the risk based quality management process. -EMA, Nov 18, 2013 Link: /11/WC pdf QRM is evolving from manufacturing and devices to clinical studies 6

7 Growing Regulatory Imperative for Systematic and Standardized Methods -- EMA Guideline on Good Pharmacovigilance Practices (GVP) Module V - Risk Management Systems Module XVI - Risk Minimisation Measures: Selection of Tools and Effectiveness Indicators risk minimisation activities should be science based and developed by suitable qualified people Where does a risk management professional go to look for a roadmap to systematic risk management? 7

8 ICH Q-9: Quality Risk Management The purpose of this document is to offer a systematic approach to quality risk management. In relation to pharmaceuticals, although there are a variety of stakeholders, including patients and medical practitioners as well as government and industry, the protection of the patient by managing the risk to quality should be considered of prime importance. FDA/ICH Q-9 offers a roadmap to achieve a systematic approach to risk management 8

9 Overview of Topics Growing regulatory imperative for systematic and standardized risk management methods Overview of ICH Q9 What Q-9 offers risk management professionals How to get started and communicate these methods to business executives 9

10 FDA/ICH Q9: Quality Risk Management Developed within the Expert Working Group (Quality) of ICH Good news: 2006 Bad news: 2006 ICH: FDA: 10

11 Table of Contents 1. Introduction 2. Scope 3. Principles of Quality Risk Management 4. General Quality Risk Management Process 5. Risk Management Methodology 6. Integration of Quality Risk Management Into Industry and Regulatory Operations 7. Definitions 8. References Annex I: Annex II: Risk Management Methods and Tools Potential Applications for QRM 11

12 I. Introduction What is Risk? Risk is the combination of the probability of occurrence of harm and the severity of that harm Shared understanding of the application of RM among diverse stakeholders is difficult because each stakeholder perceives different potential harms Different probability on each harm occurring Different severities for each harm 12

13 II. Scope Principles & examples of tools of quality risk management can be applied to different aspects of pharmaceutical quality, includes: Development Manufacturing Distribution Inspection Submission and Review Processes throughout the lifecycle of: Drug substances Quality risk management in product lifecycle management Drug (medicinal) products Biological and biotechnological products ICH Q9 13

14 III. Principles of Quality Risk Management Two primary principles: 1. The evaluation of the risk to quality should be based on scientific knowledge and ultimately link to the protection of the patient 2. The level of effort, formality and documentation of the quality risk management process should be commensurate with the level of risk Science-based Approaches and Risk-Calibrated 14

15 IV. General Quality Risk Management ICH Q9 Initiate Quality Risk Management Process Risk Assessment Risk Identification Risk Analysis Risk Communication Risk Evaluation Risk Control Risk Reduction Risk Acceptance unacceptable Risk Management Output / Result of the Quality Risk Management Process Risk Review Review Events 15

16 IV.A. Responsibilities Decision makers: Take responsibility for coordinating quality risk management across various functions and departments of their organization and Ensure that a quality risk management process is defined, deployed, and reviewed and that adequate resources are available. QRM Team: Quality risk management activities are usually, but not always, undertaken by interdisciplinary teams. When teams are formed, they should include experts from the appropriate areas (e.g., quality unit, business development, engineering, regulatory affairs, production operations, sales and marketing, legal, statistics, and clinical) in addition to individuals who are knowledgeable about the quality risk management process. 16

17 IV.B. Initiating a Quality Risk Management Process 1. Define the problem and/or risk question, including pertinent assumptions identifying the potential for risk; 2. Assemble background information and/ or data on the potential hazard, harm or human health impact relevant to the risk assessment; 3. Identify a leader and necessary resources; 4. Specify a timeline, deliverables and appropriate level of decision making for the risk management process. QRM should include systematic processes designed to coordinate, facilitate and improve science-based decision making about risk 17

18 IV.C. Risk Assessment Initiate Quality Risk Management Process Risk Assessment Risk Identification Risk Identification What might go wrong? Risk Communication Risk Control Risk Analysis Risk Evaluation Risk Reduction Risk Acceptance Output / Result of the Quality Risk Management Process unacceptable Risk Management Risk Analysis What is the likelihood and severity it will go wrong? What is the ability to detect the problem? Risk Evaluation What is the strength of the evidence? Risk Review Review Events 18

19 IV.D. Risk Control Initiate Quality Risk Management Process Risk Communication Risk Assessment Risk Control Risk Review Risk Identification Risk Analysis Risk Evaluation Risk Reduction Risk Acceptance Output / Result of the Quality Risk Management Process Review Events unacceptable Risk Management Risk Reduction - Is the risk above an acceptable level? - What can be done to reduce or eliminate the risk? Risk Acceptance - What is the appropriate balance among benefits, risks, and resources? - Are new risks introduced as a result of the identified risks being controlled? 19

20 IV.D. Risk Communication Initiate Quality Risk Management Process Risk Assessment Risk Identification Risk Analysis Risk Communication Risk Evaluation Risk Control Risk Reduction Risk Acceptance unacceptable Risk Management Sharing of information about risk and risk management between decision makers and others Output / Result of the Quality Risk Management Process Risk Review Review Events 20

21 [Quality Risk Management Triad ] 1. Risk Assessment 2. Risk Control 3. Risk Communication 21

22 V. Risk Management Methodology Basic risk management facilitation methods (flowcharts, check sheets, etc.) Failure Mode Effects Analysis (FMEA) Failure Mode, Effects, and Criticality Analysis (FMECA) Fault Tree Analysis (FTA) Hazard Analysis and Critical Control Points (HACCP) Hazard Operability Analysis (HAZOP) Preliminary Hazard Analysis (PHA) Risk ranking and filtering Supporting statistical tools Combined use provides flexibility Degree of rigor and formality should reflect available knowledge and be commensurate with the complexity and/or criticality 22

23 VI. Integration of QRM into Industry and Regulatory Operations Examples for industry and regulatory operations (see Annex II): Quality management Examples for industry operations and activities (see Annex II): Development Facility, equipment, and utilities Materials management Production Laboratory control and stability testing Packaging and labeling Examples for regulatory operations (see Annex II): Inspection and assessment activities Quality risk management should be integrated into existing operations and documented appropriately 23

24 VII. Definitions Quality risk management: A systematic process for the assessment, control, communication, and review of risks to the quality of the drug product across the product lifecycle. Decision maker(s) Detectability Harm Hazard Product lifecycle Quality Quality risk management Quality system Requirements Risk Risk acceptance Risk analysis Risk assessment Risk communication Risk control Risk evaluation Risk identification Risk management Risk reduction Risk review Severity Stakeholder Trend 24

25 Annex I: Risk Management Methods and Tools I.1 Basic Risk Management Facilitation Methods Flowcharts, Check Sheets, Process Mapping, Cause and Effect Diagrams I.2 Failure Mode Effects Analysis (FMEA) Breakdown of the analysis of complex processes into manageable steps I.3 Failure Mode, Effects and Criticality Analysis (FMECA) FMEA extended to include severity, probability, and detectability I.4 Fault Tree Analysis (FTA) Fault modes are described with logical operators (AND, OR, etc.) I.5 Hazard Analysis and Critical Control Points (HACCP) Hazard analysis with critical control points, limits, and monitoring I.6 Hazard Operability Analysis (HAZOP) Systematic brainstorming identifying hazards using guide words I.7 Preliminary Hazard Analysis (PHA) Possibilities the risk event occurs I.8 Risk Ranking and Filtering Risk comparison and prioritization I.9 Supporting Statistical Tools Control charts, design of experiments, histograms, Pareto charts, process capability analysis 25

26 Annex II: Potential Applications for Quality Risk Management II.1 II.2 II.3 II.4 II.5 II.6 II.7 II.8 Integrated Quality Management Regulatory Operations Development Facilities, Equipment and Utilities Materials Management Production Laboratory Control and Stability Studies Packaging and Labelling 26

27 Overview of ICH Q9 is Not a Driver s License Get some good guidance as you embark on your journey for quality risk management 27

28 What Does ICH Q-9 Mean For Pharmaceutical Risk Management Professionals? ParagonRx International LLC

Relevance For Risk Management Professionals Important Themes and Takeaways from ICH Q-9

improve science-based decision making with respect to risk to quality Key Features of QRM A

appropriate methods and the expertise to use them is important Two Primary Principles The

link to the protection of the patient The level of effort, formality and documentation of

29 Relevance For Risk Management Professionals Important Themes and Takeaways from ICH Q-9 Quality Risk Management Defined Systematic processes designed to coordinate, facilitate and improve science-based decision making with respect to risk to quality Key Features of QRM A team approach using science-based methods and tools to support decision making Selection of appropriate methods and the expertise to use them is important Two Primary Principles The evaluation of the risk to quality should be based on scientific knowledge and ultimately link to the protection of the patient The level of effort, formality and documentation of the quality risk management process should be commensurate with the level of risk (proportionate) 29

30 Relevance For Risk Management Professionals Important Themes and Takeaways from ICH Q-9 Applications Foundation for science-based decisions May affect the extent and level of direct regulatory oversight Prevention from overly restrictive and unnecessary requirements Facilitates communication and transparency Challenges Embed this behavior into quality aspects of business, technology and regulation Adopt in existing structures and organizations Balance the documented use of informal and formal quality risk management 30

Relevance For Risk Management Professionals Expectations of Regulators Proportionality The risk management system shall be proportionate to the identified risks and the potential risks of the

31 Relevance For Risk Management Professionals Expectations of Regulators Proportionality The risk management system shall be proportionate to the identified risks and the potential risks of the medicinal product, and the need for post-authorisation safety data EU GVP Module V The performance of these measures in healthcare systems requires assessment to ensure that their objectives are fulfilled and that the measures in place are proportionate taking account of the risk-benefit profile of the product and the efforts required of healthcare professionals and patients to implement the measures EU GVP Module XVI Science-based methods and qualified people While routine measures are applied to every medicinal product additional risk minimisation activities should only be proposed when they are laid down as conditions for the safe and effective use of the medicinal product and these should be science based, and developed and provided by suitably qualified people. EU GVP Module XVI 31

32 Relevance For Risk Management Professionals Expectations of Regulators Standardization o By the end of FY 2013, FDA will hold one or more public meetings to obtain stakeholder input on standardizing REMS to reduce the burden on the healthcare system Systematic PDUFA Reauthorization Performance Goals and Procedures Fiscal Years 2013 through 2017 o Systematic approach to benefit-risk assessment should support the work of review staff throughout the lifecycle of a drug by capturing the full range of decisions from pre-market review through any regulatory actions that are necessary in the post-market Structured Approach to Benefit-Risk Assessment in Drug Regulatory Decision-Making 32

Relevance For Risk Management Professionals Quality Risk Management Can Address Core Questions What is the best way to balance customization and standardization?

33 Relevance For Risk Management Professionals Quality Risk Management Can Address Core Questions What is the best way to balance customization and standardization? How much variation is necessary and unavoidable? How are the best interventions targeted to prevent or mitigate failures? What is the appropriate trade off between enhanced safety and additional burden to the health care system? 33

34 How to get Started? ParagonRx International LLC

35 Simplify to Start RISK ASSESSMENT 1. Map the process 2. Conduct a Systematic Risk Assessment (e.g., RCA, FMEA. HACCP) to identify potential risks and interventions 3. Define the Risk Prioritization Number to address the highest risk concerns affecting patient safety RISK CONTROL FOR FIXED RISKS Checklists Training Backup Systems Procedures FOR DYNAMIC RISKS Threshold-Triggered Actions Real-time Dashboards Audits RISK COMMUNICATION 1. Document the Risk Management Plan 2. Implement with SOPs 3. Support with change management efforts Assessment, Control, and Communication are the Triad of Risk Management in action 35

36 Target Activities Executive summary ICH Q9 QUALITY RISK MANAGEMENT When to apply Quality Risk Management? CONSIDERATIONS Should risks be assessed? Are there clear rules for decision making? e.g. regulations No or justification needed 1. What might go wrong? 2. What is the likelihood (probability) it will go wrong? 3. What are the consequences (severity)? Yes no RM Can you answer the risk assessment questions? Yes informal RM No formal RM Agree on a team (small project) Risk assessment not required (No flexibility) Initiate Risk assessment (risk identification, analysis & evaluation) Select a Risk Management tool (if appropriate e.g. see ICH Q9 Annex I) Follow procedures (e.g. Standard Operating Procedures) Run risk control (select appropriate measures) Carry out the quality risk management process Document results, decisions and actions Document the steps Based on K. Connelly, AstraZeneca, 2005 prepared by some members of the ICH Q9 EWG for example only; not an official policy/guidance July 2006, slide 36 Source: ICH Q9 Briefing Package,

37 How to Get Started: What Do Leaders Need to Do? Ensure organization is aware of ICH Q9 and the opportunity it affords Appropriate education and training Encourage open, risk aware culture Establish & support QRM leaders Coordinate implementation and resource allocation Prioritize; start small, learn as you go Adapted From: ICH Q9 Briefing Package, 37

38 FoREMS & More Occurs the second Wednesday of every month at 12:00 pm ET Topic ideas? Guest speaking opportunities? Feedback? Contact us: Jeff Fetterman Next webinar: Wednesday, April 9 38

Risk Management: FDA and Industry Experience. Dan Snider, Ph.D Vice President Morgantown RD Mylan Pharmaceuticals Inc.

Risk Management: FDA and Industry Experience Dan Snider, Ph.D Vice President Morgantown RD Mylan Pharmaceuticals Inc. Disclaimer This presentation contains a summary of the opinion and perspective from