Risk Management in Clinical Trials

1. Risk Management in Clinical Trials Sue Gregory Senior Manager, Clinical Compliance Savara ApS

2. Risk Management in Clinical Trials Competent Authority Reflections The current manner in which some elements of a quality system are implemented by sponsors and their agents (CROs etc.) is generally acknowledged to be time-consuming and constitutes a major proportion of the cost of development of medicines. The combination of these findings and the high cost of the oversight of clinical trials strongly suggests that the current approach to clinical quality management is in need of review and reorientation. there are too many trials in which avoidable quality problems arise. This is illustrated by the nature and extent of findings, identified by European GCP inspectors, during inspections.

3. Risk Management in Clinical Trials Competent Authority Reflections

4. Risk Management in Clinical Trials Competent Authority Reflections

5. Risk Management in Clinical Trials Competent Authority Reflections

6. Risk Management in Clinical Trials The sponsor should: implement a system to manage quality throughout all stages of the trial process. focus on trial activities essential to ensuring human subject protection and the reliability of trial results.  assure and control the quality of the trial using methods proportionate to the risks inherent in the trial and the importance of the information collected. ICH E6(R2) section 5.0

7. Risk Management in Clinical Trials The sponsor should: implement a system to manage quality throughout all stages of the trial process. https://www.ctti-clinicaltrials.org Clinical Trials Transformation Initiative ICH E6(R2) section 5.0

8. Risk Management in Clinical Trials The sponsor should: implement a system to manage quality throughout all stages of the trial process. focus on trial activities essential to ensuring human subject protection and the reliability of trial results.  assure and control the quality of the trial using methods proportionate to the risks inherent in the trial and the importance of the information collected. ICH E6(R2) section 5.0

9. Risk Management in Clinical Trials Quality can be defined as the absence of errors that matter to decision making

10. Risk Management in Clinical Trials ICH E6, section 5.0 Quality Management The quality management system should use a risk-based approach as described below. 5.0.1 Critical Process and Data Identification 5.0.2 Risk Identification 5.0.3 Risk Evaluation 5.0.4 Risk Control 5.0.5 Risk Communication 5.0.6 Risk Review 5.0.7 Risk Reporting

11. Risk Management in Clinical Trials Risk Based Approach 5.0.1 Critical Process and Data Identification During protocol development, the sponsor should identify those processes and data that are critical to assure human subject protection and the reliability of study results.

12. Risk Management in Clinical Trials Risk Based Approach

13. Risk Management in Clinical Trials Risk Based Approach PRO-001 as an example: Study Design: Phase III randomised, double-blind, placebo-controlled, multi-centre Efficacy of Atenefa in psoriatic arthritis patients Atenefa solution for injection, subcutaneously 3-times weekly 100mg, 150mg or placebo for 24 weeks

14. Risk Management in Clinical Trials Risk Based Approach PRO-001: Primary Objective: Efficacy of Atenefacompared to placebo by the PsoriaticArthritisresponsecriteria (PsARC) after 24 weekstreatment KeySecondaryObjectives: Proportion of subjects with dermatologist’ Global Assessment of psoriasis rating of clear or almost clear Time to onset of clinicalresponse by PsARC Effect of Atenefa on Quality of Life outcomesusing Short Form 36 (SF36) and Dermatology Life Quality Index (DLQI) Pharmacodynamiceffect of Atenefa on liver enzymes

15. Risk Management in Clinical Trials Risk Based Approach Group Exercise: Critical Process and Data Identification for PRO-001: Which processes and data are critical to assure human subject protection and the reliability of study results?

16. Risk Management in Clinical Trials Risk Based Approach

17. Risk Management in Clinical Trials Risk Based Approach 5.0.2 Risk Identification The sponsor should identify risks to critical trial processes and data. Risks should be considered at both the system level (e.g., standard operating procedures, computerized systems, personnel) and clinical trial level (e.g., trial design, data collection, informed consent process).

18. Risk Management in Clinical Trials Risk Based Approach Identifying Risks….. Safety/PV personnel Patient Associations Investigators Monitors Statisticians Trial Managers QA personnel Medical experts etc. Clinical Trial Supplies personnel Data Managers CRO representatives

19. Risk Management in Clinical Trials Risk Based Approach Identifying Risks….. IMP Related risk area: • physico-chemical properties of the active ingredient(s) • manufacturing process of the active ingredient(s) and of the IMP • pharmacokinetic, pharmacological and toxicological properties of the IMP • requirements for the labelling and packaging of the IMP Trial Design Related risk area: • complexity of trial design, • trial population (e.g. vulnerability, morbidity), • therapeutic area (e.g. difficult recruitment associated with rare disease), • sample size calculation, • practicability and adequacy of the eligibility criteria,  • non-medicinal protocol related activities (e.g. risk associated with biopsies). Ref: https://www.ema.europa.eu/documents/scientific-guideline/reflection-paper-risk-based-quality-management-clinical-trials_en.pdf

20. Risk Management in Clinical Trials Risk Based Approach Identifying Risks….. Operational risk area: • study budget (e.g. inadequate planning for resourcing monitoring or other trial activities), • development deadlines, • staff resource level and study specific training (e.g. lack of GCP experience at a trial site), • study management team and responsibilities (e.g. lack of revision of documents), • clinical trial site selection and management, • contract research organisation involvement, • clinical trial supply processes and management, • clinical site set up and infrastructure, • laboratory setup, • setup of trial databases (e.g. trial specific IVRS, eCRF with controlled access of the study eCRF and specific site training), • site monitoring and central monitoring, • management of clinical data including adapted safety monitoring (e.g. lack of SUSARS reporting), • reporting and/or communication lines. Ref: https://www.ema.europa.eu/documents/scientific-guideline/reflection-paper-risk-based-quality-management-clinical-trials_en.pdf

21. Risk Management in Clinical Trials Risk Based Approach Identifying Risks….. Interfaces of quality systems or movements of information/data Non-standard procedures New/unique tools Difficult product storage conditions Specific safety considerations Trial complexity Unknown sites …etc

22. Risk Management in Clinical Trials Risk Based Approach Identifying Risks…..

23. Risk Management in Clinical Trials Risk Based Approach Identifying Risks….. CTTI - CRITICAL TO QUALITY (CTQ) FACTORS PRINCIPLES DOCUMENT https://www.ctti-clinicaltrials.org/files/principles_document_finaldraft_19may15_1.pdf

24. Risk Management in Clinical Trials Risk Based Approach Identifying Risks….. Transcelerate Risk Assessment and Categorization Tool (RACT) https://transceleratebiopharmainc.com/assets/rbm-assets/

25. Risk Management in Clinical Trials Risk Based Approach Identifying Risks….. MHRA GCP Forum – Examples of Risk Assessments https://mhrainspectorate.blog.gov.uk/2017/11/16/risk-adaption-in-clinical-trials-of-investigational-medicinal-products-ctimps/ Examples of real-life risk assessments

26. Risk Management in Clinical Trials Risk Based Approach Formulating Risk Statements Because/If [the issue] there is a risk that [the risk] resulting in [the consequence] e.g. eDiaries BecauseeDiaries may not be validatedthere is a risk that they may fail in use and vital data are not collected resulting in incomplete data being analysed Because eDiaries may not be validatedthere is a risk that data integrity may be compromised resulting in inaccurate data being analysed Because eDiaries may not be accepted by trial participants there is a risk that data may not be entered resulting in incomplete data being analysed

27. Risk Management in Clinical Trials Risk Based Approach 5.0.3 Risk Evaluation The sponsor should evaluate the identified risks, against existing risk controls by considering: (a) The likelihood of errors occurring. (b) The extent to which such errors would be detectable. (c) The impact of such errors on human subject protection and reliability of trial results.

28. Risk Management in Clinical Trials Risk Based Approach Risk is defined as the combination of the probability of occurrence of harm and the severity of that harm. Ask: 1. What might go wrong? 2. What is the likelihood it will go wrong? 3. What are the consequences? 4. How easy it is to detect?

29. Risk Management in Clinical Trials Risk Based Approach Prioritising risks – risk ranking….

30. Risk Management in Clinical Trials Risk Based Approach Prioritising risks – risk ranking….

31. Risk Management in Clinical Trials Risk Based Approach Prioritising risks – risk ranking…. Example 10-level scale for likelihood and severity https://www.ecrin.org/sites/default/files/Risk-based%20monitoring%20toolbox/Guideline%20on%20risk%20management%20for%20clinical%20research_1.0_2015_02_16.pdf

32. Risk Management in Clinical Trials Risk Based Approach Risk is defined as the combination of the probability of occurrence of harm and the severity of that harm. Ask: 1. What might go wrong? 2. What is the likelihood it will go wrong? 3. What are the consequences? 4. How easy it is to detect?

33. Risk Management in Clinical Trials Risk Based Approach Prioritising risks – risk ranking…. Example 10-level scale for likelihood, severity and detectability High score levels associated with low detectability https://www.ecrin.org/sites/default/files/Risk-based%20monitoring%20toolbox/Guideline%20on%20risk%20management%20for%20clinical%20research_1.0_2015_02_16.pdf

34. Risk Management in Clinical Trials Risk Based Approach Risk Criticality: Involves likelihood, impact and detectability. e.g.: • Risk Criticality = Likelihood x Impact x Detectability • or • Risk Criticality = Likelihood x Impact  Detectability used to inform risk control activities

35. Risk Management in Clinical Trials Risk Based Approach Prioritising risks – risk ranking….

36. Risk Management in Clinical Trials Risk Based Approach Group exercise – based on the protocol synopsis and critical data or processes for PRO-001 (Atenefa), identify 2 or 3 risks and: Formulate a risk statement (issue, risk, consequence) Estimate the likelihood it will occur Describe how it would be detected

37. Risk Management in Clinical Trials Risk Based Approach

38. Risk Management in Clinical Trials Risk Based Approach 5.0.3 Risk Control The sponsor should decide which risks to reduce and/or which risks to accept. The approach used to reduce risk to an acceptable level should be proportionate to the significance of the risk. Risk reduction activities may be incorporated in protocol design and implementation, monitoring plans, agreements between parties defining roles and responsibilities, systematic safeguards to ensure adherence to standard operating procedures, and training in processes and procedures. Predefined quality tolerance limits should be established, taking into consideration the medical and statistical characteristics of the variables as well as the statistical design of the trial, to identify systematic issues that can impact subject safety or reliability of trial results. Detection of deviations from the predefined quality tolerance limits should trigger an evaluation to determine if action is needed.

39. Risk Management in Clinical Trials Risk Based Approach Risk Control Oversight mechanisms: e.g. Data Monitoring Committees, Trial Steering Committee etc. Management mechanisms: e.g. Training, trial-specific plans & procedures etc. Monitoring Strategy e.g.: Centralised: data validation, statistical data surveillance, medical (AE) review etc. Off-Site: query management, timeliness of data entry, track recruitment/enrollment etc. On-site: Informed Consent Review, Eligibility verification, Safety review, IMP accountability, SDV

40. Risk Management in Clinical Trials Risk Based Approach Source Data Verification limitations: Published error rate for human inspection is 15% 100% inspection is approximately 85% effective Consider also: Information subject doesn’t report Cultural factors that affect what the subject will report Information reported but considered of no consequence Reporting only adverse ‘reactions’ Data in patient charts with primary healthcare provider Tantsyura et al, Therapeutic Innovation & Regulatory Science, 2015, Vol 49(6) 903-910

41. Risk Management in Clinical Trials Monitor’s responsibilities – ICH E6

42. Risk Management in Clinical Trials Risk Based Approach Monitoring activities should focus on preventing or mitigating important and likely sources of error in the conduct, collection, and reporting of critical data and processes necessary for human subject protection and trial integrity. The monitoring strategy may involve central tools to identify the need for targeted monitoring visits based on assessment (statistical or other) of centrally accrued data and information. These processes provide additional monitoring capabilities that can complement and justify adaptations to the extent and/or frequency of on-site monitoring. EC Risk proportionate approaches in clinical trials

43. Risk Management in Clinical Trials Risk Based Approach “Risk Management is not about minimal effort – it’s about best effort!”

44. Risk Management in Clinical Trials Risk Based Approach Based on the risk assessment the intensity and focus of monitoring could vary, e.g. : MHRA Good Clinical Practice Guide, 2012

45. Risk Management in Clinical Trials Risk Based Approach Prioritising risks – risk ranking….

46. Risk Management in Clinical Trials Risk Based Approach 5.0.5 Risk CommunicationThe sponsor should document quality management activities. The sponsor should communicate quality management activities to those who are involved in or affected by such activities, to facilitate risk review and continual improvement during clinical trial execution. 5.0.6 Risk Review The sponsor should periodically review risk control measures to ascertain whether the implemented quality management activities remain effective and relevant, taking into account emerging knowledge and experience. 5.0.7 Risk Reporting The sponsor should describe the quality management approach implemented in the trial and summarize important deviations from the predefined quality tolerance limits and remedial actions taken in the clinical study report.

47. Risk Management in Clinical Trials Risk Based Approach

48. Risk Management in Clinical Trials Risk Based Approach • Prospectively identify critical data and processes • Perform risk assessment to identify and understand the risks that could affect the collection of critical data or the performance of critical processes • Develop a monitoring plan that focuses on the important and likely risks to critical data and processes • Implement an escalation plan that responds dynamically to identified risks and tolerance limits

49. Risk Management in Clinical Trials Risk Based Approach References: FDA Guidance for Industry: Oversight of Clinical Investigations — A Risk-Based Approach to Monitoring : http://www.fda.gov/downloads/Drugs/.../Guidances/UCM269919.pdf EMA Reflection paper on risk based quality management in clinical trials (EMA/269011/2013) : http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/11/WC500155491.pdf TransCelerate Risk Based Monitoring : http://www.transceleratebiopharmainc.com/initiatives/risk-based-monitoring/ ICH Quality Risk Management, Q9 : http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q9/Step4/Q9_Guideline.pdf EC Risk proportionate approaches in clinical trials https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-10/2017_04_25_risk_proportionate_approaches_in_ct.pdf Examples of risk assessments: http://forums.mhra.gov.uk/showthread.php?1678-Examples-of-risk-assessments CTTI Critical to Quality Factors principles document: https://www.ctti-clinicaltrials.org/files/principles_document_finaldraft_19may15_1.pdf ECRIN Guideline on risk management for clinical research: https://www.ecrin.org/sites/default/files/Risk-based%20monitoring%20toolbox/Guideline%20on%20risk%20management%20for%20clinical%20research_1.0_2015_02_16.pdf