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Monitoring and Audit in Clinical Trials

Wednesday 31st August 2016

Anna Barnett

In Chesterfield

In today’s session

1. Monitoring: What is and why do we do it?

2. At Site Monitoring: How do we do it?

3. Audit: What is it and how is it different from monitoring?

Generally: Why these are important for you and what you can expect

Section 1

Monitoring: What is and why do we do it?

Attacked by a duck on the way to Stamford GP site

What is Monitoring?

Monitoring is one of several functions used to ensure the quality of clinical trials:

–Monitoring –Audit – Inspection – SOPs

View of Dundee on flight from Stansted

Quality Assurance

Monitor

Audit

Inspect

Quality Assurance

Monitor

Audit

Inspect

Ongoing operational quality control

Snapshot of trial status with completed CAPA

Regulatory review for compliance with UK SIs – routine or triggered

Monitoring is a legal requirement

• All clinical information shall be recorded, handled and stored in such a way that it can be accurately reported, interpreted and verified, while the confidentiality of records of the trial subjects remains protected.

• UK Statutory Instrument 2004/1031 (as amended), Schedule 1, Part 2, 9

• Subject to paragraph (5), the sponsor shall put and keep in

place arrangements for the purpose of ensuring that with regard to that trial the conditions and principles of good clinical practice are satisfied or adhered to.

• UK Statutory Instrument 2004/1031 (as amended), Regulation 28, (2)

Monitoring is defined in ICH GCP

“The act of overseeing the progress of a clinical trial, and ensuring that it is conducted, recorded, and reported in accordance with the protocol, SOPs, GCP and regulatory requirements”

(ICH GCP 1.38)

A common misconception is that only clinical trial monitors perform

monitoring

Various Monitoring formats

Oversight of a trial can be through various different formats including:

– Committees

– Trial Management Groups

– At site monitoring

– Remote/phone based monitoring

– Centralised monitoring/data review

All these different formats are considered to be forms of monitoring and thus the monitoring of a trial may

involve a large number of different staff

What activities comprise “central monitoring” of a clinical trial and

should they be documented? • Eg. GOVERNANCE: Any relevant/important communication or contact

relating to the conduct of the trial by the sponsor would be part of monitoring the trial and this oversight, be it telephone calls, emails or letters should be documented and must be retained and this would also demonstrate regular contact with the investigator(s).

• Eg. DATA MANAGEMENT: The investigator site will submit the clinical data CRFs either using eCRF or faxing/sending paper CRFs. Any generated evidence of central monitoring activities regarding this data must be retained, these could include reports generated from interrogating the database, for example, looking at data submission timeliness, audit trails of the eCRF to examine times of completion, data query rates and response timeliness, SAE reporting rate, comparisons/reconciliations with other databases (e.g. IVRS, Central Labs) and data from other sites.

There should be a formal process for dealing with issues and data queries identified during central monitoring and data management activities, including an escalation process.

Risk assessment is used to determine the type and frequency of monitoring

• Trial specific to assess hazards: – Risks to participant safety from IMP – Risks to reliability of results – Risks from trial clinical procedures – Risk to patient rights: consent & protection of personal

data – Risks to compliance • Mitigate or accept risks (Risk Management Planning) • Use to develop the protocol and the OVERSIGHT &

MONITORING STRATEGY to manage risk

Section 2

At site monitoring: How do we do it?

Flight from Dundee

“At site” monitoring has 3 objectives

• To verify that the rights and well-being of human subjects are protected

• To ensure reported trial data are accurate, complete and verifiable from source data

• To ensure the trial is compliant with protocol, ICH GCP, regulatory requirements

Christmas market Birmingham

In practical terms this means...

• Monitors will look at: Informed consent Source data verification of your

CRF and SAE reports against the medical records

Ensure your TMF/ISF is appropriate and complete

Check other aspects of GCP such as the training and qualification of the staff

Ensure drug accountability has been carried out in accordance with Annex 13

In Lincoln, early morning

Monitoring (of all types) is an ongoing process throughout the duration of

the trial • Facilitates training and improvement

• Trial Managers and Clinical Trial Monitors see many different trials and will have valuable knowledge about how other trials or other sites in the same trial have solved problems etc – can provide valuable guidance and support to trial teams

The trial monitor and other staff are “on your side” to help you keep everything in shape and to reassure you

that you are conducting the trial well

At GP site, Edinburgh

Preparing for a monitoring visit

• 1. Agree the date and provide support with travel arrangements

• 2. Ensure access to electronic medical records and a computer from which to view

• 3. Make paper medical records available

• 4. Ensure TMF/ISF is up to date, review it beforehand

• 5. Book a room or quiet area of an office for the monitor to work

• 6. Welcome – this person may have had a long journey

Bugs: Common findings from at site monitoring visits

• Incorrect completion of consent forms

• Incomplete delegation & signature log

• TMF not up to date

• Incomplete documentation of Training

• CRF completion not sufficiently diligent

• Not scoring through, dating and initialling errors in the CRF

• Source data unsigned by the PI

Insect in Chesterfield

Outcome of “at site” and “remote” visits

• All “at site” and “remote” monitoring visits are reported

• Site staff are provided with a list of action points and are required to respond and sign off that they have completed the requested actions

The end of the line in Lowestoft

Expectations of the MHRA

• RESPONSE/REACTION: Results of centralised monitoring and “at site” monitoring visits should be effectively utilised to guide the management of the trial

• ADAPTATION: Trials with problems should receive increased monitoring or increased oversight by other means

Everyone involved in the trial should take an interest in the monitoring findings and be responsive to the

recommendations

Please remember

• The paperwork for a trial must be able to stand in isolation to enable

– The complete reconstruction of the trial

– And to prove that the trial was conducted to ICH GCP and UK SIs

Accompanied monitoring visit: Is Darth Vader on the train?

• Therefore....

– Knowing that something was done is not enough

– If it’s not written down and filed, it never happened

If you are not accurately documenting what you are doing then you might as well not bother doing it

View from hotel, Wellingborough

Monitoring approach is evolving

High level of “at site monitoring” Risk-based site monitoring

Centralised monitoring and sponsor oversight

2001 2004 2009 2011 2012 2013 2016

CT Directive Implementation of CT Directive

FDA and EMA publish risk based approach

Transcelerate consortium

High cost Lower cost

“Adaptive” site monitoring

Centralised monitoring should be used to target “at site” monitoring

• Recognised flags: – Low data reliability – Slow data flow rate – High volume of missing data – Site compliance to protocol eg. to visit schedule – Disproportionate number of SAE reports – Disproportionate number of protocol deviations – Site staff change – Very high recruitment – High number of reports of technical issues/questions – Breaches/Serious breaches – Perceived risk

Targeted use of monitoring resource for efficiency and optimal benefit

Monitor sites, data, subjects and events that require more attention and focus

Challenges: Assessment Communication Resource Planning

Navigating the tube strike with low phone battery

Change direction

Section 3

Audit: What is it and how is it different from monitoring?

Audit process

‘A systematic and independent examination of trial-related activities and documents to determine whether the evaluated trial-related activities were conducted, and the data recorded , analysed and accurately reported according to the protocol, Sponsor’s SOPs, GCP and the applicable regulatory requirements’

(ICH GCP 1.6)

Audit is a time defined exercise to bring a trial into a GCP compliant

status

Audit can be used • On a regular basis in a trial as a “second check” in addition to

monitoring

• As a remedial exercise for problem sites

• At the end of trial to ensure the trial can be archived with confidence

Why is my trial being audited?

• 1. Routine mid point audit

• 2. Trial has ended – final audit

• 3. Monitoring has revealed a compliance problem

• 4. Inspection by the regulatory agency is scheduled

What does the auditor wish to see?

• Compliance with SOPs, policies & regulations

• High quality research

• Safety obligations met

Process and Follow up • Audit of study by:

- reviewing all essential documents and processes

- staff interaction at open and close

• Producing an audit report that:

- documents findings

- may recommend corrective actions

The auditor expects to resolve all findings as quickly as possible

Comparison: Monitoring vs Audit Aspect Monitoring Audit

Perspective Overseeing progress Assesses historical progress and reviews related systems

Communication Ongoing relationship One off – set up of audit and performance feedback, CAPA

Training Responsibility Not a responsibility but may be an outcome of audit

Site facility review All aspects reviewed on ongoing basis Assesses during audit

Site electronic systems Ongoing review Review of key systems at point of audit

SDV Yes Reviews sample and process itself

Consent Reviews 100% Reviews, % varies

IMP Verifying all IMP appropriately supplied to site, handled, stored, accounted for and returned/destroyed.

Opportunity to review at global, site and subject level, on sample basis.

Adverse events Determining whether all adverse events occurring at the site are appropriately reported, within required timeframes.

Review on sample basis, sample biased to include SAEs when they occur.

Issues To identify and ensure resolution of all site issues.

To highlight issues and advise on process improvement.

Conclusion

• Clinical trials can be monitored, audited and inspected at any time – be ready

• Good, structured documentation is key (TMF = Three Messy Folders?)

• Monitors are here to help – please contact us! (We never agree

with you about a shortcut or bypass of a process though)