1. Monitoring and Auditing
Dr Ruben E. Keane
Trinity Centre, St James Hospital, Dublin
30 January 2015

2. Whats my responsibility as investigator?
Monitoring and Auditing are Sponsor responsibilities
So why does the investigator have to think about them?
Investigator/sponsor
Academic institutions as sponsors
Sponsor can delegate responsibilites
‘The investigator/ institution should permit monitoring and auditing by the sponsor and inspection by the approprite regulatory authority(ies)’
(ICH GCP 4.1.4)
If sponsor responsibility why do investigators have to think about them.
Well, as we will see Academic institutions are only coming to grips with the idea of academic sponsorship

3. What is Monitoring?
The act of overseeing the progress of a clinical trial, and of ensuring that it is conducted, recorded and reported in accordance with
The protocol
Standard Operating Procedures (SOPs)
Good Clinical Practice (GCP) and
the applicable regulatory requirements
(ICH GCP 1.38)
You as Investigator probably wrote the protocol – if you deviate from it consider amending it!

4. Why Monitor? ICH GCP and ISO14155 requirement.
To verify that:
the rights and well being of participants are protected
the reported clinical trial data are accurate, complete and verifiable from source documents
The conduct of the trial is in compliance with
The currently approved protocol/ammendment(s)
With Good Clinical Practice
With applicable regulatory requirements
(ICH GCP 5.18.)
Note – currently approved protocol – ensure amendments are done if procedures change.
Applicable regulatory requirements – Regulations EU , ISO 190
Devices directives etc.–

5. Who should Monitor? Monitors should be appointed by the Sponsor.
Monitors should be appropriately trained and have the scientific and/ clinical knowlege needed to monitor the trial adequately.
Need to be familiar with IMP, Protocol, GCP etc.
(ICH GCP )
Science, Nursing or Medical qualifications.
Training in ICH-GCP, regulations, monitoring techniques
Training in Therapeutic area and protocol
Sponsor may delegate the responsibility for appointing a monitor to the PI.

6. Who Currently Monitors academic trials?
A member of the study team
Contract Research Organisations (CRO)
Freelance Contract monitors
HRB Clinical Research Facilities – Monitoring resources – Reciprocal monitoring - ICTRN

7. Nature and extent of Monitoring:
‘ Adequately monitored’ (ICH-GCP )
This depends on the purpose, nature, complexity of design, size, risk to patients, endpoints, experience of PI and study site personnel.
Traditionally Gold standard monitoring
on site visits every 4- 8 weeks
100% Source Document Verification
Traditional monitoring – onsite visit ever 4-8 weeks Move towards risk based central data monitoring – more targeted use of resources – fewer on site visits

8. Move toward Risk Based Central Data Monitoring:
FDA guidance doc (2013) and EMA reflection paper (2011)
Maximise use of resources , increase efffectiveness– more scrutiny of data, centrally and fewer onsite visits.
Some data anomalies more easily detected by central monitoring techniques.
Effective remote monitoring enabled by technology:
Electronic CRF
Real time data entry
SKYPE remote ‘visits’
Traditional monitoring – onsite visit ever 6-8 weeks Move towards risk based central data monitoring – more targeted use of resources – fewer on site visits

9. Types of on site Monitoring Visits
Site Selection
Site initiation
Ongoing monitoring – routine or targeted visits
Close out visit
Monitor= main communication link between sponsor and investigator
Monitoring report to sponsor and follow up letter to PI after each visit
Site selection – verify suitability of the investigator and site
Do they have the necessary facilities and personnel and time to carry out the study.
Targeted visit – if issues identified at site by remote data monitoring, by monitor , by Sponsor etc

10. Site Selection
Purpose: Verify the suitability of the investigator and the site
Investigator and study staff qualifications and experience
Clinical trial experience, experience in therapteutic area
Adequate site resources and facilities
Any specialised equipment needed,
storage and dispensing of IMP
Adequate patient population
Site selection – verify suitability of the investigator and site
Do they have the necessary facilities and personnel and time to carry out the study.

11. Site Initiation
Purpose: To ensure site is ready to begin entering patients
Investigational Medicinal product on site
Clinical supplies on site
Training on Protocol , GCP, study specific procedures
Data Collection
AE/ SAE reporting
Informed consent
Investigator site file - documentation
Site selection – verify suitability of the investigator and site
Do they have the necessary facilities and personnel and time to carry out the study.
Site initiation-IMP on site, site personnel training , delegation log, Essential documents ready to start – green light
Ongoing routine monitoring- check informed consents, CRFs, Do SDV (%) , check IMP storage and accountability, Essential documents. SAE reporting
Close out visit- Any outstanding data queries, drug accountability and destruction, Essential documents complete, archiving arrangements for sample storage,

12. Ongoing- Routine Monitoring
Monitor will focus on key study processes and documents:
Informed consent process and documents – often 100% review
Essential documents –including Approvals from Ethics Committee and Regulatory authorities, Insurance, Sponsor agreement etc
Qualifications, experience and training of site personnel
Patient data - Study endpoints
Eligibility pf patients– Inclusion and exclusion criteria
Safety data -Adverse events (AE, SAE) documentation,reporting and follow up.
Some errors are more important than others!

13. Key processes and documents (Continued)
Investigational Medicinal product or device – handing, storage, accountability
Completion of Case Report forms – accurate and timely
Sample Collection and handling
Source document verification for % of participants
Data management procedures – data capture and query resolution

14. Close out visit
Purpose: To ensure that all documentation is complete, queries resolved and IMP accounted for.
Review the Investigator site file
Discuss Archiving
IMP – final accountability and destruction/return.
Sample storage/ destruction
Site selection – verify suitability of the investigator and site
Do they have the necessary facilities and personnel and time to carry out the study.
Site initiation-IMP on site, site personnel training , delegation log, Essential documents ready to start – green light
Ongoing routine monitoring- check informed consents, CRFs, Do SDV (%) , check IMP storage and accountability, Essential documents. SAE reporting
Close out visit- Any outstanding data queries, drug accountability and destruction, Essential documents complete, archiving arrangements for sample storage,

15. Monitoring plan
Who will monitor ?– consider qualificaitons and experience
How often?
Remote or onsite?
What will be monitored? - some errors are more important than others…
What % of source document verification?
Quality by Design- build quality into the planning phase.
Some errors more important than others – consider an error in e.g patient height compared to an error in measuring a study endpoint or not reporting an SAE

16. Audit
A sytematic and independent examination of trial related activities and documents to determine whether the evaluated trial related activities were conducted, and the data were recorded, analyzed and accurately reported according
to the protocol,
sponsors standard operating procedures (SOPs),
Good Clinical Practice (GCP) ,
and the applicable regulatory requirements.
(ICH GCP 1.6)

17. Monitoring versus Audit
Ongoing review of quality
Snap shot of compliance
Focus on data and daily activities of site
Focus on Processes and systems
Monitor is part of study team
Auditor is independent
Flag issue and suggest remedial action
Evaluate if remedial action is working
Monitoring report + follow up letter
Audit report noting non compliances
Reply to follow up letter
Corrective and Preventive action plan (CAPA)

18. If monitoring is done well, why audit?
Objectivity- Auditor is not part of the study team
Audit is more process focussed
Audit -Overview -Looking at the forest versus the tree!
Audit -Can assess the effectiveness of monitoring
Monitoring may trigger an audit – systemic problem
Audit can support the monitor in getting compliance from unresponsive sites
Audit can support study site in preparing for regulatory inspection

19. Academic studies wrt monitoringand auditing:
Challenges:
Resources - Lack of experienced monitors and auditors on the study team
Costs- no cconsideration of Monitoring and Auditing costs in grant applications
Clarity re who is responsbile for monitoring -Who takes on this sponsor responsibility?
Monitoring multicentre studies – language/culture/travel
Opportunities:
Clinical research facilities -Monitoring capabilities – reciprocal monitoring - ICTRN
Awareness to factor in Monitoring and Auditing in grant application/costings
Quality by desing- Monitoring/ Quality Plan at early planning stage.
Increased clarity around sponsorship responsibilities.

20. UCC sponsored HPRA studies
Sponsor (UCC) Green light procedure
Before study can start recruiting QRM visits site to review documentation and processes. CRRO signs off green light.
Quality Plan drawn up by Investigator and QRM at this visit:
Who will monitor and how often
Qualifications and experience of monitor
Who will do Pharmacovigilance
Who will do Data management
Who will Audit and how often
Who’s SOPs will be used
Archiving arrangements

21. Monitoring + Auditing – Synergy - addative effect on Quality
Both are vital components in the sponsors Quality Assurance and Quality Control Processes.
Monitoring and Audit are support functions who share your objectives
of ensuring patient rights and safety
ensuring data is accurate and credible
getting good quality clinical research done well
helping you prepare for inspections