1. Risk Management in Clinical Trials
Sue Gregory
Senior Manager, Clinical Compliance
Savara ApS
NORM Meeting Sept 2019

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.
NORM Meeting Sept 2019

3. Risk Management in Clinical Trials
Competent Authority Reflections
NORM Meeting Sept 2019

4. Risk Management in Clinical Trials
Competent Authority Reflections
NORM Meeting Sept 2019

5. Risk Management in Clinical Trials
Competent Authority Reflections
NORM Meeting Sept 2019

6. Risk Management in Clinical Trials
ICH E6(R2) section 5.0
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.
NORM Meeting Sept 2019

7. Risk Management in Clinical Trials
ICH E6(R2) section 5.0
The sponsor should:
implement a system to manage quality throughout all stages of the trial process.
Clinical Trials Transformation Initiative
NORM Meeting Sept 2019

8. Risk Management in Clinical Trials
ICH E6(R2) section 5.0
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.
NORM Meeting Sept 2019

9. Risk Management in Clinical Trials
Quality can be defined as the absence of errors that matter to decision making
NORM Meeting Sept 2019

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
NORM Meeting Sept 2019

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.
NORM Meeting Sept 2019

12. Risk Management in Clinical Trials
Risk Based Approach
Support primary objectives
Critical to subject safety
Support key secondary objectives
Support decision making about IMP efficacy
Critical Data
Underpin data quality
Underpin subject safety
Support ethical and GCP compliance
Critical Processes
NORM Meeting Sept 2019

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
NORM Meeting Sept 2019

14. Risk Management in Clinical Trials
Risk Based Approach
PRO-001:
Primary Objective:
Efficacy of Atenefa compared to placebo by the Psoriatic Arthritis response criteria (PsARC) after 24 weeks treatment
Key Secondary Objectives:
Proportion of subjects with dermatologist’ Global Assessment of psoriasis rating of clear or almost clear
Time to onset of clinical response by PsARC
Effect of Atenefa on Quality of Life outcomes using Short Form 36 (SF36) and Dermatology Life Quality Index (DLQI)
Pharmacodynamic effect of Atenefa on liver enzymes
NORM Meeting Sept 2019

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?
NORM Meeting Sept 2019

16. Risk Management in Clinical Trials
Risk Based Approach
PRO-001 Critical Data includes
PRO-001 Critical Processes include
- Physician’s assessment of response (PsARC)
- Dermatologist’s assessment of psoriasis
- Dermatologist’s qualifications
- Subject’s assessment of QoL
- Study medication compliance
- Lab results for liver enzymes
- Key eligibility criteria:
¤History of condition
¤Baseline status of condition
¤Liver enzymes ….
- Informed Consent
- Randomisation
- Maintaining the blind
- Study medication storage and reconciliation
- Study medication administration
- Performance of PsARC
- Performance of Global Assessment
- Lab sample collection and management
- AE collection and reporting
NORM Meeting Sept 2019

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).
NORM Meeting Sept 2019

18. Risk Management in Clinical Trials
Risk Based Approach
Identifying Risks…..
Safety/PV personnel
Patient Associations
Investigators
Monitors
Statisticians
QA personnel
Trial Managers
Medical experts
Clinical Trial Supplies personnel
etc.
Data Managers
CRO representatives
NORM Meeting Sept 2019

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:
NORM Meeting Sept 2019

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:
NORM Meeting Sept 2019

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
NORM Meeting Sept 2019

22. Risk Management in Clinical Trials
Risk Based Approach
Identifying Risks…..
Critical element
Example risk considerations
Subjective endpoint (e.g. rater scales)
Rater qualifications; training; inter-rater consistency; ensuring correct person performs the assessments etc
Objective endpoint (e.g. lab value)
Conditions for maintaining sample integrity; lab methods and reporting; scheduling to ensure sample is taken etc
Patient Reported Outcomes
Training; provision of technology; assessment of PRO data for AEs; ensuring the PRO is completed etc
IMP
Stability [storage conditions (temperature, lighting, security)]; point of use (clinic, subject’s home); Preparation (as is or reconstituted); Administration (topical, intravenous etc); availability (automatic resupply?);
Informed Consent
Multiple ICF versions; consent/assent; ethics approvals; adequacy of process documentation; qualifications of person performing interview etc
Specific data point
ALCOA standards (Attributable, Legible, Contemporaneous, Original, Accurate); integrity of data capture method, validation of calculations etc
NORM Meeting Sept 2019

23. Risk Management in Clinical Trials
Risk Based Approach
Identifying Risks…..
CTTI - CRITICAL TO QUALITY (CTQ) FACTORS PRINCIPLES DOCUMENT
NORM Meeting Sept 2019

24. Risk Management in Clinical Trials
Risk Based Approach
Identifying Risks…..
Transcelerate Risk Assessment and Categorization Tool (RACT)
NORM Meeting Sept 2019

25. Risk Management in Clinical Trials
Risk Based Approach
Identifying Risks…..
MHRA GCP Forum – Examples of Risk Assessments
Examples of real-life risk assessments
NORM Meeting Sept 2019

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
Because eDiaries may not be validated there 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 validated there 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
NORM Meeting Sept 2019

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.
NORM Meeting Sept 2019

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?
NORM Meeting Sept 2019

29. Risk Management in Clinical Trials
Risk Based Approach
Prioritising risks – risk ranking….
Likelihood
Low
Medium
High
Impact
High Impact
Medium Risk
High Risk
Medium Impact
Low Impact
Low Risk
NORM Meeting Sept 2019

30. Risk Management in Clinical Trials
Risk Based Approach
Prioritising risks – risk ranking….
Likelihood
Negligible (1)
Low (2)
Moderate (3)
High (4)
Excessive (5)
Impact 5 10 15 20 25 4 8 12 16 3 6 9 2 1
NORM Meeting Sept 2019

31. Risk Management in Clinical Trials
Risk Based Approach
Prioritising risks – risk ranking….
Example 10-level scale for likelihood and severity
level
Likelihood
Impact 1
Impossible
Inconsequential 2
Extremely improbable
Barely perceptible 3
Very improbable
Very limited 4
Improbable
Limited 5
Unlikely
Sensitive 6
Possible
Significant 7
Probable
Very significant 8
Very probable
Important 9
Extremely probable
Very important 10
Certain
Disastrous
NORM Meeting Sept 2019

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?
NORM Meeting Sept 2019

33. Risk Management in Clinical Trials
Risk Based Approach
Prioritising risks – risk ranking….
Example 10-level scale for likelihood, severity and detectability
level
Likelihood
Impact
Detectability 1
Impossible
Inconsequential
Certain 2
Extremely improbable
Barely perceptible
Extremely Probable 3
Very improbable
Very limited
Very Probable 4
Improbable
Limited
Probable 5
Unlikely
Sensitive
Possible 6
Significant 7
Very significant 8
Very probable
Important 9
Extremely probable
Very important 10
Disastrous
High score levels associated with low detectability
NORM Meeting Sept 2019

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
NORM Meeting Sept 2019

35. Risk Management in Clinical Trials
Risk Based Approach
Prioritising risks – risk ranking….
Critical process/data No.
Risk Number
What could cause The Failure (because /if…)
Risk description / Failure mode
(There is a Risk that…)
Consequence / Effect
(resulting in...)
Likeli-hood
Impact
Detectability
Criticality Scoring 1
1.01
Patients are hospitalised and it might not be clear when an SAE should be reported
SAEs are not reported in time
Critical safety information is not shared with Authorities and participating sites in time. 2 5 3
Only detectable through source data
10 (30)
1.02
The life threatening state of the patients, many events will happen that could be interpreted as adverse events
Overreporting of adverse events
collecting too many data that do not add value.
Central review of listings with MedDRA coding information
3 (6)
NORM Meeting Sept 2019

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
NORM Meeting Sept 2019

37. Risk Management in Clinical Trials
Risk Based Approach
PRO-001 Critical Data includes
PRO-001 Critical Processes include
- Physician’s assessment of response (PsARC)
- Dermatologist’s assessment of psoriasis
- Dermatologist’s qualifications
- Subject’s assessment of QoL
- Study medication compliance
- Lab results for liver enzymes
- Key eligibility criteria:
¤History of condition
¤Baseline status of condition
¤Liver enzymes ….
- Informed Consent
- Randomisation
- Maintaining the blind
- Study medication storage and reconciliation
- Study medication administration
- Performance of PsARC
- Performance of Global Assessment
- Lab sample collection and management
- AE collection and reporting
NORM Meeting Sept 2019

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.
NORM Meeting Sept 2019

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
NORM Meeting Sept 2019

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)
NORM Meeting Sept 2019

41. Risk Management in Clinical Trials
Monitor’s responsibilities – ICH E6
Investigator qualifications
IMP Storage Conditions
Subject Eligibility
IMP Accountability and Disposition
Protocol Compliance
Written Consent
Source Data Accuracy
Verifying…
Act as link between Sponsor and Investigator
Protocol Deviations
SOP Deviations
GCP Deviations
Communicating….
Provision of trial supplies
Provision of Investigator’s Brochure and trial documents
Site staff adequately trained
Errors corrected properly
Ensuring….
Accuracy of CRF entries
Documentation of dosing
Adverse Events are recorded
Missed visits are documented
Withdrawals and dropouts are explained
Checking….
Subject recruitment rate
Significant findings
Deviations
Actions taken
Reporting….
Investigator about errors
Site staff about trial, trial procedures, amendments etc.
Informing…
Whether Adverse Events have been reported
Whether essential documents have been maintained
Determining…
NORM Meeting Sept 2019

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.
NORM Meeting Sept 2019
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!”
NORM Meeting Sept 2019

44. Risk Management in Clinical Trials
Risk Based Approach
Based on the risk assessment the intensity and focus of monitoring could vary, e.g. :
High intensity if…
Low intensity if…
Sample processing/
handling
Sensitivity of sample analysis dependent on sample handling – e.g. PK samples linked to primary objective
Sample handling will have no impact on reliability of results - e,g. samples linked to exploratory endpoints
Investigational Medicinal Product
Compliance / storage critical for endpoints
e.g. Licenced product used within licenced indication – especially if stored at ambient temperature
Data and source data verification
Large proportion of data are considered critical e.g. safety, primary / secondary endpoints. Especially early phase trials, pivotal trials for MAAs or where publications could result in major change to clinical practice
Accuracy of data will not have significant impact on results or there are good QC processes in place
Investigator site experience
Inexperienced investigators and/site staff
Experienced investigators and/site staff
MHRA Good Clinical Practice Guide, 2012
NORM Meeting Sept 2019

45. Risk Management in Clinical Trials
Risk Based Approach
Prioritising risks – risk ranking….
Critical process/data No.
Risk No.
What could cause The Failure (because/ if…)
Risk description / Failure mode
(There is a Risk that…)
Consequence / Effect
(resulting in...)
Before Control
Control
After Control
Likeli
hood
Impact
Detectability
Criticality Scoring
likelihood
Criticality scoring 1
1.01
Patients are hospitalised and it might not be clear when an SAE should be reported
SAEs are not reported in time
Critical safety information is not shared with Authorities and participating sites in time. 2 5 3
Only detectable through source data
10 (30)
Mitigate: Intensive monitoring while on-site
5 (10)
1.02
The life threatening state of the patients, many events will happen that could be interpreted as adverse events
Overreporting of adverse events
collecting too many data that does not add value.
Central review of listings with MedDRA coding information
3 (6)
Risk accepted
NORM Meeting Sept 2019

46. Risk Management in Clinical Trials
Risk Based Approach
5.0.5 Risk Communication The 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.
NORM Meeting Sept 2019

47. Risk Management in Clinical Trials
Risk Based Approach
Risk assessment
Data surveillance
Dynamic monitoring
NORM Meeting Sept 2019

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
NORM Meeting Sept 2019

49. Risk Management in Clinical Trials
Risk Based Approach
References:
FDA Guidance for Industry: Oversight of Clinical Investigations — A Risk-Based Approach to Monitoring :
EMA Reflection paper on risk based quality management in clinical trials (EMA/269011/2013) :
TransCelerate Risk Based Monitoring :
ICH Quality Risk Management, Q9 :
EC Risk proportionate approaches in clinical trials
Examples of risk assessments:
CTTI Critical to Quality Factors principles document:
ECRIN Guideline on risk management for clinical research:
based%20monitoring%20toolbox/Guideline%20on%20risk%20management%20for%20clinical%20research_1.0_2015_02_16.pdf
NORM Meeting Sept 2019

50. NORM Meeting Sept 2019