MHRA produced FAQs for monitoring

[MHRA Super Moderator]

18. Is it necessary to perform an investigator site initiation visit?

The site research team musta be suitably trained to undertake the trial activities. There should be a documented process to demonstrate that the sponsor has ensured that the investigator site research team is suitably trained, set up and ready to conduct the trial. Whilst this is often done with a specific initiation visit and sometimes a meeting of investigators, this may not always be necessary. Specific training could be done centrally via telephone or video-conferencing or using web-based approaches. Training and initiation packages could be sent to the site containing manuals/instructions and checklists to complete and return. The level of training needed would be dependent upon the experience of the site staff and the complexity of the trial. The level of instruction given to the trial site staff at this stage and during the initial stages of conducting the trial is likely to influence the compliance level of the site. Remote training may have risks as it will be reduced in length and may be harder for the trainer to identify any lack of understanding, particularly if it is done without any interaction (e.g. web presentation). The sponsor is recommended to retain evidence of the training given and ideally, evidence of the effectiveness, i.e. the understanding of the site staff, of the training provided. Again, it is recommended that the risk assessment considers the need for site initiation and training. It is also recommended that there is the means to address the training of new staff or re-training of existing staff if the need arises.

a. SI 2004/1031 (as amended) Regulation 28 (1) and (2), Schedule 1, Part 2, (2)

Version 1: 22 February 2013

[MHRA Super Moderator]

19. Is it necessary to perform an investigator site close out visit?

The close out visit by a monitor would primarily be to ensure all the trial documentation and source data is appropriately filed and stored for future retrieval if necessary, to ensure that all trial materials and IMP is accounted for and returned/destroyed, that all the necessary trial data and documentation have been collected and that there are no outstanding monitoring issues or data queries. Some or all of this could be undertaken remotely, with the investigator site staff undertaking tasks under instructions from the sponsor, for example completing checklists for the contents of the investigator file. If the site has been visited before, then the archiving storage should have been assessed and no further visit needed or alternatively, the archiving could be arranged at an archiving vendor by the sponsor (see TMF FAQs). Again, it is recommended that the risk assessment considers the need for close down visits and how the investigator TMF and source data will be available for the required retention time, as this must^a be available for at least 5 years.

a. SI 2004/1031 (as amended) Regulation 31A

Version 1: 22 February 2013

[MHRA Super Moderator]

20. What activities comprise “central monitoring” of a clinical trial and should they be documented?

Central monitoring activities, focussing on the areas that matter as identified in the monitoring strategy could be undertaken by numerous roles and across various departments, for example clinical operations, study management, data management, statistics, medical monitoring etc. with close co-operation where appropriate. It is recommended that where the sponsor is undertaking many trials, some generic central monitoring processes are contained in SOPs, rather than trial specific documents.

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^a be retained and this would also demonstrate regular contact with the investigator(s).

There will be many documents received from the investigator sites as per the monitoring procedures, these could include: consent/eligibility documents, status reports (recruitment/withdrawals etc), self assessment questionnaires/checklists. The sponsor should ensure that processes are in place to ensure blinding of the trial is maintained if documentation that could potentially unblind the trial is to be handled in central monitoring activities, for example records sent from pharmacy. Any generated evidence that receipt and review of such information has taken place must^a be retained and as such this could prevent the need to retain the actual copies of the documents received. Some non-commercial trials use a form of central monitoring that involves sending in information from the investigator site to a central data centre. It is important that if information that identifies a subject is sent, for example copy of consent form, for monitoring purposes, that the subject has given explicit consent for this and is aware of who will have access to their data and this process is recommended to be included in the protocol. A formal system should be in place at the receiving site to restrict access to confidential subject data with respect to compliance with the Data Protection Act. Compliance any local country-specific requirements will also be required.

Additionally, 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^a 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. The investigator musta retain the original source document or a certified copy and the sponsor should not have exclusive control of a source document.

The data validation activities, usually done by data management, would be expected to be documented and so must^a be retained; this would include evidence of manual checks of CRFs and outputs of inconsistencies detected from data validation systems. It is recommended that the data validation activities are recommended to be focussed on the data that is critical to the reliability of the trial results as identified by the risk assessment rather than excessive resource spent on raising data queries whose resolution makes little or no impact on the quality of the trial, the safety of the subjects and reliability of the results. This is similar to the approach taken for proportionate source data verification (SDV) (see FAQ 26).

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. Any generated evidence of identification of the issue(s), review and discussion and subsequent actions must^a be retained. The monitoring strategy and procedures must^b be followed and there should be documentary evidence of this.

The use of central monitoring transfers some additional activities to the investigator site and may impact on site resources; however, the investigator and research team must^c conduct the trial in accordance with the principles of GCP and have some specific responsibilities they must^d undertake according to the legislation. Some of the additional activities needed for central monitoring may assist in ensuring that this occurs (e.g. completing a checklist for review of investigator site file contents).

The MHRA is willing to publish examples here of central monitoring documentation (for example plans and output reports) to assist sponsors in developing processes and procedures. Sponsors, who wish to provide examples for consideration for publication, should contact the MHRA GCP Inspectorate: GCP.inspectors@mhra.gsi.gov.uk
The examples are not intended to be definitive approaches. They are not endorsed or recommended by the MHRA.

a. SI 2004/1031 (as amended) Regulation 31A (3)
b. SI 2004/1031 (as amended) Regulation 28 (1) and (2), Schedule 1, Part 2, (4)
c. SI 2004/1031 (as amended) Regulation 28 1(a)
d. SI 2004/1031 (as amended) Regulations 12, 13, 14, 29 (a), 31 A (7) & (8) and 32

Version 1: 22 February 2013

[MHRA Super Moderator]

21. What is statistical monitoring?

Statistical monitoring is an aspect of central monitoring. Sometimes this term can be used in relation to a sequential trial design with respect to analysis for stopping rules, but this is not what is being considered here, which relates to monitoring the conduct of the trial. It is where the accumulating data, either clinical data from the CRF, for example SAE event rates or performance data, for example eCRF completion times obtained from audit trail, data query levels/response timeliness and CRF return times are examined using statistical approaches or modelling across the trial. This allows comparisons of sites to occur and this trending, modelling and process control has the aim of identifying any unusual or extraordinary patterns/variance/distributions within the data and in particular if any sites appear to be “outliers”. Some statistical monitoring can use multivariate methods whereby the data from many variables can be used simultaneously to identify outlying sites. The aim of the methodology is to use the information to decide where to target potential increased monitoring such as on-site visits, telephone calls, training etc and there may be predefined criteria or tolerance limits in the derived parameters which would trigger further monitoring activities or corrective/preventative actions. Outputs from the statistical monitoring usually take the form of graphs.

The use of all the data in this manner can potentially reveal issues that on-site monitoring might not detect, for example potential fraud. Statisticians have traditionally been involved in trial design and data analysis, but an expansion in use of central monitoring is likely to develop new roles in this area for statisticians. It will also increase the necessary interaction between monitoring, data management and others with statistics personnel.

The MHRA is willing to publish examples of statistical monitoring documentation/reports to assist sponsors in developing processes and procedures. Sponsors, who wish to provide examples for consideration for publication here, should contact the MHRA GCP Inspectorate: GCP.inspectors@mhra.gsi.gov.uk

Version 1: 22 February 2013

The examples are not intended to be definitive approaches. They are not endorsed or recommended by the MHRA

[MHRA Super Moderator]

22. Are there any expectations of which metrics or key performance indicators or methodologies should be used in central/statistical monitoring?

It is understood that many organisations are developing quality metrics or key risk/performance indicators to assist in determining which investigator site to visit, often this is part of the audit function rather than monitoring, but there does not appear to be a list of accepted or validated metrics for sponsors to use. The methodology would include ranking investigator sites with respect to the metrics to identifying outlying sites. Some organisations are also using multivariate statistical methodologies enabling the use of several metrics simultaneously. It is recommended that the methods and metrics to be used are documented in the monitoring procedures. Some sponsors have used the following metrics:

• Recruitment rate
• Screen failure rates
• CRF submission/completion times against actual patient’s progress in the trial
• Query rates
• Time to queries resolution vs number of active queries (site level)
• SAEs reported
• Numbers of missed or late visits/data
• Number of Subject withdrawals/dropouts
• Numbers of protocol/GCP non-compliances recorded/reported
• eCRF – audit trail information on completion times in relation to visits or expected timescales

The MHRA is willing to publish further examples of metrics/methodologies being used to assist sponsors in developing processes and procedures and undertaking research. It is possible that organisations may be undertaking similar approaches already. Sponsors, who wish to provide examples for consideration for publication here, should contact the MHRA GCP Inspectorate.

The MHRA encourages further research and publications into the use of key performance indicators and statistical methodology and validation of their effectiveness in the identification of non compliant sites. Sponsors undertaking such research are encouraged to contact the GCP Inspectorate.

GCP.inspectors@mhra.gsi.gov.uk

Version 1: 22 February 2013

The examples are not intended to be definitive approaches. They are not endorsed or recommended by the MHRA

[MHRA Super Moderator]

23. What are the benefits of conducting an on-site visit?

Central monitoring may cover many of the tasks that a monitor would undertake at site provided the appropriate and genuine documentation has been provided by the investigator. There are, however, some key benefits of undertaking an on-site visit which include:

• Reviewing patient medical records (e.g. when central remote electronic review is not possible by the sponsor) - to conduct SDV, verify the existence of a subject; verifying the existence and quality of source documents and detect unreported adverse events
• Meeting, training and motivating the research team and the investigator
• Interviewing staff face to face, which builds rapport and can determine the actual processes used at the site (and any issues associated with that) rather than only conducting a review of the outcome (documentation) that may not present the whole picture
• Reviewing facilities and equipment
• Establishing the role of the investigator in the trial conduct (e.g. monitoring the delegation of duties and the investigator’s involvement and oversight of the trial)
• Providing an overall impression of the quality of the conduct of the trial at the site, which may enable action to be taken to improve quality at an earlier stage
• Reviewing IMP storage areas and performing any necessary accountability checks on the actual IMP (this may only be a sample (initially), if considered appropriate in the risk assessment)
• Reviewing investigators’ site file (Investigator’s TMF) and archive facilities
• Mentoring new staff/investigators
• Witnessing subject visits – e.g. consenting process

If such considerations are identified as vulnerabilities in the trial risk assessment, then this would impact on the decision to undertake on-site monitoring and make it more likely to be needed. For example, for a trial categorised as a Type C, with little safety information in patients, on-site visits to check for adverse events in the notes is more important than in a trial categorised as a Type A where the IMP is well known and used in accordance with standard clinical practice. It should be noted that on-site monitoring does not necessarily need frequent regular visits (e.g. traditionally once every 4-8 weeks), the interval between visits could be set at an appropriate level based on risk assessment, for example, the sites could be visited once, shortly after starting the trial or on a fairly infrequent basis, with a more targeted approach to monitoring activities based on the outcomes seen at previous visits or from central monitoring.

Version 1: 22 February 2013

[MHRA Super Moderator]

24. How should non-compliance be dealt with when it is identified?

There should be a formal process to identify, assess and document any non-compliance, i.e. failure to comply with the protocol, GCP or the legislation, which is identified through the monitoring activities. This is to protect the rights and well-being of the trial subjects and the integrity of the trial results. Ability to do this is also necessary to comply with the requirements of serious breach reporting, as some non-compliances must^a to be reported to the MHRA.

Actions could include increasing site monitoring intensity/frequency, visits to site by sponsor senior management, conducting an audit, holding or terminating recruitment at the site until the non-compliance issue is resolved (such temporary halting of recruitment at a site may constitute an Urgent Safety Measure)– e.g. by re-training, additional resources etc. The corrective and preventative actions to deal with the non-compliance should be documented and they should be followed up to ensure that they are completed as per a formalised escalation process and in a timely manner. In many MHRA GCP inspections it has been found that where non-compliance issues have been found at investigator sites by the monitor there has been a failure to address them in a timely manner and to an appropriate resolution. There should be a mechanism to ensure that all the non-compliance is documented such that it can be reviewed as part of the analysis of the data for impact on the trial results and details provided in the clinical study report/publication.

a. SI 2004/1031 (as amended) Regulation 29A

Version 1: 22 February 2013