1. Bringing the Risk Based Approach to the eTMF
Andy Lawton,
Risk Based Approach Ltd
September 12, 2019

2. Abstract
The release of ICH E6 R2 brought the risk based approach to the clinical development area as well as several other concepts - Risk Assessment, Risk Based Monitoring, QTL’s, etc. Many people consider that the only area to impact the TMF is section 8 of ICH E6 R2, but it is important to look holistically at all the changes as well as the impending changes to ICH E8 (draft May2019). This presentation will examine the driving concepts behind the ICH changes as well as the impact of the detailed changes.

3. Topics ICH E6 background The gaps identified. Structural
Non structural
The gaps identified.

4. Drivers for ICH E.6 Addendum changes
Concerns over quality from Regulatory Authorities
Lack of trust for ICH-GCP statements in submission based on Audits
We claim “all trials conducted to ICH-GCP”, but results from inspections always show GCP issues
Upset over lack of transparency
Lack of focus on real risks
Want defined quality
Want Quality by Design, not “Quality by Accident”
Quality throughout the organisation – not as isolated islands(silos)
Lack of demonstrable oversight
Poor “Root cause analysis”
“Stupidity of 100% SDV” as solution, CRA misses “helicopter” view of site
Pharma is wasting resources

5. Quality Metrics Data for QMS in clinical?
ICH E.6 Future
The
FUTURE?
FDA draft Guidance 11/2016
Quality Metrics Data
FDA Guidance ?2022
Quality Metrics Data for QMS in clinical?
ICH E6 “Renovation”
3 Annexes for E6
ICH Q
ICH E.6 Release
ICH E.6
R2 D1
2015
ICH E.6
R2 D2
2015
ICH E.6 Final 2016
FDA RBA Draft Guidance
2011
FDA RBA Final Guidance
2013
ICH E.8 R1
May 2019
EMA RBA Draft Guidance
2011
EMA RBA Final Guidance
2013

6. Centralized Monitoring
New for Sponsor in ICH E.6
Sponsor
Quality Management
Risk Based Approach
Non Compliance
Quality by Design
CRO Oversight
Monitoring
Nature of Monitoring
Centralized Monitoring
Monitoring Plan
Monitoring Report
Electronic Media
Computerized Systems
Essential Documents
Certified Copy

7. New \ changed for Investigator in ICH E.6
Delegation of Tasks
Supervision
Qualified
CSV – Audit Trail
Essential Documents
Source Documents and Trial Records
Maintain adequate / accurate
ALCOA

8. Regulatory documents Document Release Emphasis
FDA and EMA draft Guidance
2011
Risk Based Monitoring
EMA Final Guidance
2013
Quality Management and Quality Tolerance Limits
ICH E6 R2
Nov 2016
Quality Management, Risk Based Approach, RBM and Quality Tolerance Limits
ICH E6 renovation announced
Jan 2017
Extension of ICH beyond RCT and Critical To Quality (CTQ)
FDA Q&A draft
Mar 2019
Integrated Monitoring plan containing all aspects
ICH E8 R1 draft
May 2019
Next slides

9. ICH E8 D1 - main points Quality by Design Quality Culture
Risk Assessment
Quality Attributes
Critical To Quality
Quality Culture
Drug development innovations

10. ICH E8 D1 - Quality by Design
Risk Assessment
Good Design
Good Execution
Control procedures to manage risk
Communication to stakeho;ders
Quality Attributes
Requirements - Involve patient
Requirements - Involve Regulatory bodies
Start in pre-clinical,
Critical To Quality
Avoid
Overreliance on QA – checklists, auditing, monitoring, retrospective document checking

11. ICH E8 D1 - Quality by Design
Quality Culture
Avoid an overreliance on QA – checklists, auditing, monitoring, retrospective document checking
Promote an open dialogue – Quality issues should be openly discussed so as to prevent future occurrence
Internal issues e.g. Poor design
External issues e.g. misconduct / potential fraud
Knowledge management
Build on knowledge and experience
Reward and value critical thinking
? Quality Tolerance Limits

12. ICH E8 D1 - Drug Development Innovations
Product Development plan
Not just Clinical Development Plan
This follows on from developing Quality Attributes and Critical to Quality, start at initial concept not at start of clinical development
Development path
Do not have to follow traditional paths, can use innovations
e.g. Use historical controls rather than use placebos
Consider Observational and Epidemiology trials (part of ICH E6 renovation)

13. Mats Welin, Senior Expert, EMA
16 April 2015

14. ICH E.6 GCP Details considered relevant are covered in next 25 slides
Left hand column has the extract from V2 Step 4 of ICH E.6 Addendum
Right hand column has my commentary
Only focus on key points

15. 8 ESSENTIAL DOCUMENTS FOR THE CONDUCT OF A CLINICAL TRIAL
8.1 Introduction The sponsor and investigator/institution should maintain a record of the location(s) of their respective essential documents including source documents. The storage system used during the trial and for archiving (irrespective of the type of media used) should provide for document identification, version history, search, and retrieval. Essential documents for the trial should be supplemented or may be reduced where justified (in advance of trial initiation) based on the importance and relevance of the specific documents to the trial.
RBA should be applied to essential documents, with lower requirements for less important documents, or drop completely for some trials (consider role of Quality Tolerance Limits here)

16. 8 ESSENTIAL DOCUMENTS FOR THE CONDUCT OF A CLINICAL TRIAL
8.1 Introduction (continued) The sponsor should ensure that the investigator has control of and continuous access to the CRF data reported to the sponsor. The sponsor should not have exclusive control of those data. When a copy is used to replace an original document (e.g., source documents, CRF), the copy should fulfill the requirements for certified copies. The investigator/institution should have control of all essential documents and records generated by the investigator/institution before, during, and after the trial.
Internal definition required as to what “control” means, and what can a sponsor do with the data on route to submission.
Define Certified Copy
Control still required after end of trial – difficult!

17. ICH Introduction
Since the development of the ICH GCP Guideline, the scale, complexity, and cost of clinical trials have increased. Evolutions in technology and risk management processes offer new opportunities to increase efficiency and focus on relevant activities. When the original ICH E6(R1) text was prepared, clinical trials were performed in a largely paper- based process. Advances in use of electronic data recording and reporting facilitate implementation of other approaches. For example, centralized monitoring can now offer a greater advantage, to a broader range of trials than is suggested in the original text. Therefore, this guideline has been amended to encourage implementation of improved and more efficient approaches to clinical trial design, conduct, oversight, recording and reporting while continuing to ensure human subject protection and reliability of trial results. Standards regarding electronic records and essential documents intended to increase clinical trial quality and efficiency have also been updated.
To address as general point in the QMS, that processes are going to be more efficient and ensure safety, i.e define safety level via QTL (not perfection) and measure efficiency

18. 1.63 Certified Copy
A copy (irrespective of the type of media used) of the original record that has been verified (i.e., by a dated signature or by generation through a validated process) to have the same information, including data that describe the context, content, and structure, as the original.
The section had a lot of discussion in Lisbon ICH meeting in June2016 so we saw this as the final version – hence the additional bracketed text on the first line.
Important to define in an SOP, what forms a paper certified copy and electronic certified copy

19. 1.65 Validation of computerized systems
A process of establishing and documenting that the specified requirements of a computerized system can be consistently fulfilled from design until decommissioning of the system or transition to a new system. The approach to validation should be based on a risk assessment that takes into consideration the intended use of the system and the potential of the system to affect human subject protection and reliability of trial results.
Not RBM specific, but a clear focus for CSV and note the addition of a risk assessment to take into account the use of the system.

20. 2 THE PRINCIPLES OF ICH GCP
2.10 This principle applies to all records referenced in this guideline, irrespective of the type of media used.

21. 2 THE PRINCIPLES OF ICH GCP
New text, but following the principles already set out that processes as well as data should follow a risk based approach
2.13 Systems with procedures that assure the quality of every aspect of the trial should be implemented. ADDENDUM Aspects of the trial that are essential to ensure human subject protection and reliability of trial results should be the focus of such systems.

22. 5.5 Trial Management, Data Handling, and Record Keeping
5.5.3 When using electronic trial data handling and/or remote electronic trial data systems, the sponsor should:
Ensure and document that the electronic data processing system(s) conforms to the sponsor’s established requirements for completeness, accuracy, reliability, and consistent intended performance (i.e., validation).
ADDENDUM
The sponsor should base their approach to validation of such systems on a risk assessment that takes into consideration the intended use of the system and the potential of the system to affect human subject protection and reliability of trial results.
Use a Risk Based Approach with CSV

23. 5.5 Trial Management, Data Handling, and Record Keeping
Basic CSV
… but ensure all parties understand their responsibilities, in particular Investigator and site
5.5.3 (b) Maintains SOPs for using these systems. ADDENDUM The SOPs should cover system setup, installation, and use. The SOPs should describe system validation and functionality testing, data collection and handling, system maintenance, system security measures, change control, data backup, recovery, contingency planning, and decommissioning. The responsibilities of the sponsor, investigator, and other parties with respect to the use of these computerized systems should be clear, and the users should be provided with training in their use.

24. 5.5 Trial Management, Data Handling, and Record Keeping
(h) Ensure the integrity of the data including any data that describe the context, content, and structure. This is particularly important when making changes to the computerized systems, such as software upgrades or migration of data.
Again basic CSV, but the emphasis is on ensuring that the audit trail information is maintained – Data Integrity is not just the data, but the context of recording it, and this has to be maintained.
An example would be if importing TMF documents from a CRO, are you maintaining the original audit information in your eTMF or only bringing in the documents.

25. Q & A Contact: w.a.lawton@ich-e6.co.uk
Confidential