Approaches to Risk-Based Quality Management Quality by Design/Quality Systems

Transcription

1 Your Partner in Quality Management Approaches to Risk-Based Quality Management Quality by Design/Quality Systems F-Crin Workshop on Risk Management in Clinical Trials Peter Schiemann, PhD Clinical Quality & Risk Management Expert Widler & Schiemann Ltd., Zug Switzerland 24 September 2013, Paris 1

2 Agenda Two Principles of QRM (Quality Risk Management) and QbD (Quality by Design) A Glimpse at what FDA and EMA say QbD as a Condition of QRM and Study Management Common Errors in applying QRM and QbD to Risk- Based Monitoring Change Management Aspects 2

3 Two Principles of QRM and QbD 3 Your Partner in Quality Management

4 Ultimate Goals of Quality Management Principles and Goals in the World of Health Care The Focus Patient Safety, Rights and Integrity in all clinical trials and post-marketing activities Data Integrity of data created in these clinical trials and postmarketing activities 4

5 The Concept of the Design Space applied to Clinical Trials and Pharmacovigilance 5

6 Manage the Design Space 6

7 Manage the Design Space 7

8 Manage the Design Space X X 8

9 Two Principles of QRM & QbD and a Corollary Isolated Errors do not matter! Errors that are understood do not matter! Systematic and Process Errors DO matter! 9

10 A Glimpse at What FDA and EMA say 10 Your Partner in Quality Management

11 Build quality in from outset Borrow on concepts from manufacturing sector (e.g. ICH Q9, Q10) Cycle of Plan-Do-Check-Act Detect and correct problems in real(or close to real) time Leveraging existing data and information in a systemic way Allow for prioritization of limited resources 11

12 QbD in Clinical Trials Protocol* is the blueprint for quality *Associated implementation plans (e.g., monitoring plan, communication plan, data handling plan, etc.) are also key 12

13 GDP Good Decision-making Practice The EMA Reflection Paper on QbD and QRM Clinical research is about generating information to support decision making All steps of a clinical trial are contributing to the decision making, some are formalized by legislation & GCP Protocol design Submission to IRBs and CAs (competent authorities) Initiation of trial Informed consent Oversight of risk benefit of the trial Trial reporting Finalization of CSR Submission or publication 13

14 The EMA Reflection Paper on QbD and QRM Decisions are made at various levels on the basis of knowledge founded on the data Each decision will only be as good as the processes used to collect, analyze, interpret and report it. 14

15 Risk Control/Mitigation What can be done to reduce or eliminate risks? What are the tolerance limits for identified risks? What is the appropriate balance among benefits, risks, and resources? Have pre-defined risk mitigation strategies for control of risk when trending suggests tolerance limits may be exceeded, or are exceeded, been developed and have individuals/groups that own each process been identified? Is new risk introduced as a consequence of control/mitigation strategies that are put in place? Has flexibility needed to deal with unexpected risks that may be encountered? 15

16 Risk Review How will risks be tracked - system for detection of significant problems in real time Centralized monitoring, on site monitoring, quality auditing, other? Metrics? Frequency of review? 16

17 Quality Tolerance Limits Establish the acceptable variation or tolerance limits for the clinical trial procedures involved Bearing in mind the statistical design of the trial and the potential impact of the different levels of variability on the power of the trial Trial data Trial protocol procedures and GCP Trial management procedures 17

18 Reporting Quality Clear qualitative and quantitative report Extent the trial has operated within the tolerance limits Conducted to an acceptable level of quality Prospective communication with the regulators 18

19 QbD as a Condition of QRM and Study Management 19 Your Partner in Quality Management

20 Risk-based Quality Management What question is the protocol seeking to answer? What does really matter? What might go wrong? What is the probability it will go wrong? How easy is it to identify if it does? What are the consequences if it does? 20

21 APPROACHES Trial Design and Trial Initiation Trial Conduct Data Evalution and Writing of Clinical Trial Report Regulatory Submissions and/or Publications Prioritization and risk mitigation approaches across several dimensions: Protection of trials subjects - Rights and Integrity, Safety Credibility of data and results Stratified according to knowledge of product (MA status). Customized approach depending on: Protocol complexity Therapeutic indication and nature of endpoints, including population and co-medications Administration of the product, dose, formulation Complexity of study procedures and measurement, including the nature of the intervention Vulnerability of the study population 21 21

22 Quality by Design: Study set-up How does this help? Objectives Support Senior Management and study teams with information on study design-based risk levels Prior to study start During study conduct Provide standard approach to assess study quality risk level allowing comparison across studies Offer guidance to study teams to mitigate high and medium risk levels Scope Conducts risk assessments in first step of study value chain: Study Set-up Can be applied to all studies: Countries, Marketing, early and late Development Phase I-IV (global and local) Sponsored and supported Interventional and non-interventional 22

23 Retrieval of data occurs along different risk assessment categories - selection of categories based on study type requirements Study Design Study Conduct Study Close-out Study Environment Medication Pharmacovigilance/ Safety Sampling Tailored Questionnaires for Sponsored Interventional Studies Sponsored Non-Interventional Studies Supported Interventional Studies Supported Non-Interventional Studies (in development) Risk Assessment Categories 1 Regulatory Budget Randomization/Data Outsourcing/ Contracts applied not applied Not all of the listed risk assessment categories apply to all different study types Process & Documents Feasibility/ Recruitment Registry Relationship to External Sponsor Report 23

24 Risk Analysis for all Risk Universe Entities is the central activity for cross functional teams Risk Identification & Data Gathering Qualitative & Quantitative Risk Assessment Definition of Mitigating Actions Gathering and integration of quality and risk data from a multitude of databases and other sources (e.g. Audit reports, CAPA reports, ongoing quality initiatives, etc.) in order to identify focus areas and entities Prioritizing an entity s quality and risk data by assessing its impact, Impact likelihood and detectability X along a transparent set of criteria (scoring Likelihood along high, medium, X low ) Detectability Defining the set of quality improving and risk mitigating actions in prioritized entities (using the full spectrum of available measures, e.g. training, audits, etc.) For each risk, description of chosen measures in terms of priority, rationale, etc. Driven by Quality representatives Supported by Business Partners Increasing interaction of Quality and Business Partners 24

25 Analysis of existing data for a Continuous Risk Evaluation Use the existing data to identify areas with increased quality risks Safety data # S/AEs Wealth of Existing Data Trial info Clinical data QRM Dashboard Allowing for different views: Product/Project View Process View Geographical View 25

26 Risk Indicator: Monitoring Visits delayed Illustrative Study: XYZ Risk Indicator: Delayed Monitoring Is monitoring sufficient and on time? Clinical Trial Center Month weeks Monitoring within 10 Weeks After first patient enrolled or previous monitoring visit weeks weeks First patient enrolled Monitoring visit 26

27 Risk Indicator: Premature Terminations above Protocol Average Illustrative Study: XYZ Risk Indicator: Premature terminations of patients Is there an unusual high rate of early unexpected patient drop-outs at any site? Average drop-out per patient for a site against the protocol average Measures average drop-out per patient for a site against the protocol average Threshold 1.3 x Protocol Average Protocol Average Clinical Trial Centers 1) excl. death, illness,.. 27

28 Your Partner in Quality Management Common Errors in applying QRM & QbD to Risk based Monitoring 28

29 Common Pitfalls No data driven decision matrix No upfront acceptance and rejection criteria No upfront decision algorithm, e.g. On site monitoring evidences deviations Deviations < x% no action indicated Deviations > x% but < y% phone contact Deviations > y% root cause analysis & systemic CAPA 29

30 Common Pitfalls Decision about conclusions from risk based monitoring activities left to the monitor Inconsistencies in decision making between studies without rationale for differences No clear strategy about centralized monitoring Centralized monitoring based on available data and not essential data 30

31 Change Management Aspects 31 Your Partner in Quality Management

32 Change Management Tasks Re-invent study design and planning Re-invent study management Re-invent monitoring Re-invent auditing Senior Management buy in 32

33 Change Management Tasks Re-invent study design & planning, e.g. Verify study Rationale, Objectives & Procedures Assess risks before activating any sites Learn from past experience sites AND processes as cause of non-compliance Chose only those service providers who do actually promote a risk based approach Re-invent study management Use all tools effectively Deploy monitors & project staff where it is really needed 33

34 Change Management Tasks Re-invent monitoring Train monitors to accept and deal with residual errors Re-invent site monitoring Re-invent source document verification SDV no longer a QC but a QA tool On-site monitoring to enrich data from centralized monitoring On-site monitoring visits to confirm or reject conclusions from centralized monitoring 34

35 Change Management Tasks Re-invent auditing Audits as a root cause analysis tool when Study Monitoring reveals systemic deficiencies Structured routine audits to assess plausibility of error levels Stress Test Audits to verify robustness of 35

36 Change Management Tasks Senior Management buy-in Funding Resources Support Win the hearts and minds of those in the trenches Change Management starts when Risk based Study Management is being considered! 36

37 Contact Details Peter Schiemann, PhD Managing Partner Widler & Schiemann Ltd. Weinberghöhe 10 B CH 6300 Zug Switzerland Mobile: peter.schiemann@wsqms.com 37