Monitoring and AuditingDr Ruben E. Keane

Trinity Centre, St James Hospital, Dublin

30 January 2015

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)

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)

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.)

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 5.18.2)

– Science, Nursing or Medical qualifications. – Training in ICH-GCP, regulations, monitoring techniques– Training in Therapeutic area and protocol

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

Nature and extent of Monitoring:

• ‘ Adequately monitored’ (ICH-GCP 5.18.3 )

• 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

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’

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

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 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

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.

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

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

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.

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)

Monitoring versus AuditMonitoring 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)

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

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/travelOpportunities: • 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.

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

• 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