SOP for Clinical Trial Monitoring

Objectives

The objective of this SOP is to establish quality standards for the preparation, conduct, and follow-up of monitoring visits during a clinical trial.

Monitoring is defined as 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, SOPs, GCP, and the applicable regulatory requirements.

The purpose of monitoring is to verify that:

• The rights and well-being of the human subjects are protected.
• The reported trial data are accurate, complete, and verifiable from source documents.
• The conduct of the trial is in compliance with the currently approved protocol/amendments, GCP and the applicable regulatory requirements.

Monitoring has an integral role in the QC of the clinical trial and is designed to verify the ongoing quality of the study.

Background

In accordance with the Good Clinical Practice Guideline ICH-GCP E6, continuous monitoring is an indispensable instrument in the quality assurance of a clinical trial.

Regular visits to the trial site, as well as telephone and written contact with the trial staff at the site are conducted to ensure that: the trial is conducted in accordance with the trial protocol and GCP and above all, the safety and rights of the trial subjects are verified. Problems at a trial site can be recognized at an early stage and solved. 

Monitoring will be conducted by the CRA team and overseen by the Manager or delegate.

Definition

Adverse Event (AE): Any untoward medical occurrence in a subject to whom a medical product has been administered, including occurrences which are not necessarily caused by or related to that product.

Case Report Form (CRF): A printed, optical, or electronic document designed to record all of the protocol required information to be reported to the sponsor on each trial subject.

Clinical Trial: Any investigation in human subjects, other than a non-interventional trial intended to discover or verify the clinical, pharmacological or other pharmacodynamic effects of one or more medical products or to identify any adverse reactions to one or more such products and to study absorption distribution, metabolism, and excretion in one or more such products with objective of ascertaining the safety or efficacy or those products.

Clinical Research Associates (CRAs): Part of quality team who ensure compliance with GCP, other regulatory requirements, protocol, and SOPs, by monitoring clinical trial.

Informed Consent Form (ICF):

The document which is signed by the participant/legal representative as well as the person who conducted the informed consent discussion confirming the volunteers willingness to participate in the particular trial after having been informed of all aspects of the trial that are relevant to their decision.

Investigator Site File (ISF): A standard filing system which allows the effective storage and location of essential documents related to an individual trial site.

Investigational Medicinal Products (IMP): A pharmaceutical form of an active substance or placebo being tested, or used as a reference in a clinical trial. This includes a medicinal product which has a marketing authorization but is, for purpose of the trial: 

1. Used or assembled (formulated or packaged) in a way different from the form of the product authorized under the authorization.
2. Used for a indication not included in the summary of product characteristics under the authorization for that product, or
3. Used to gain further information about the form of that product as authorized under the authorization.

Standard Operating Procedure (SOP): Detailed, written instructions to achieve uniformity of performance of a specific function. SOPs are the base on which Quality System and Processes are conducted and monitored against.

Quality Team:

Comprises the Manager, Clinical Research Associates (CRAs), and training executives.

Monitoring Plan: A document detailing how all the monitoring activities for the trial will carried out based upon the trial risk assessment.

Monitoring Visit Report (MVR): A report written by CRA to the sponsor (or representative) after each site visit.

Principal Investigator (PI): A registered physician, who has the responsibility for conduct of the trial at the site.

Trial Master File (TMF): A standard filing system which allows the effective storage and location of essential documents. The filing system can be in the form of a single project file or a number of files, depending on what are deemed most appropriate for a particular clinical trial given its size and complexity. The regulatory documents and approvals with in the TMF will be maintained alongside case report forms and source documentation.

Process

The quality team can assume responsibilities on behalf of the sponsor/CRO for the clinical trail activities provided this is agreed in advance. (e.g. by contract or authorisation)

1. Determination of Time of Visit

Dates and frequency of visits depend on the trial and site (e.g. depending on the recruitment rate, data quality) or is determined by contractual agreements, the protocol or definitions in the monitoring manual from sponsor/CRO.

It is recommended to perform the first monitoring visit after initiation of the trial site as early as possible, usually after enrolment and documentation of the first subject. This enables identification of site-specific problems with trial conduct at an early stage and avoids errors.

2. Preparation

The following points should be covered when making an appointment:

• At least one person from the trial site involved in the conduct of the trial, who is qualified to make changes or additions to the CRF, must be present.
• Time required for pure monitoring activities/for discussions with the investigator/site staff
• Current status of site (enrolled/withdrawn/completed subjects) and site-specific problems
• Trial materials required, including trial medication
• Documents that the site should provide

ALSO READ: Screening and Recruitment of Clinical Research Subjects

The appointment should be confirmed in writing with the trial site, and if appropriate, for a second time shortly before the planned visit.

The monitor should familiarise himself or herself with the content of the following documents to prepare for special situations or requirements at the site:

• Monitoring report of the previous visit
• Any follow-up correspondence, deficiency lists from previous visit
• Correspondence since the last visit
• Reports on serious adverse events requiring follow-up or which have to be reported at defined intervals to the ethics committee or competent higher federal authority.
• Status of documents (CRF, queries).

All documents and materials to be given to the investigator are put together.

3. Conduct

3.1 General Activities

Based on the study site monitoring visit checklist, the following points are to be revised during the monitoring visit:

• CRA/delegate will ensure that the investigator provides all required reports, notifications, applications and submissions and that these documents are accurate, complete, timely, legible, dated and identify the trial.
• The ISF/TMF including all essential documents
• Investigator and other team members have adequate qualifications, resources and facilities, including laboratories, equipment and staff and these remain adequate throughout the study period.
• All trail functions are performed as designated and not delegated to unauthorised individuals.
• Informed consent was obtained and documented prior to subject participation in the trial.
• Inclusion/Exclusion criteria
• Documentation of subject status
• CRFs (review and CRF status)
• Protocol compliance
• Staff changes
• Documentation of adverse events and serious adverse events as well as reporting of these in accordance with regulations
• Documentation of source data
• Trial medication (if applicable)
• Logistics of laboratory samples (if applicable)
• Documentation of trial site status
• Investigator site file
• Status of pending points of previous monitoring visits
• Documentation of protocol deviations
• Adverse events, concomitant medications and concurrent illness are reported in accordance with protocol.
• All SAEs are appropriately reported within the time period required by GCP, protocol and other applicable regulatory requirements.
• All withdrawals and dropouts of enrolled subjects from the trial are reported and explained properly.

3.2 Source Data Verification

CRF entries to source documents such as medical records, laboratory reports, ECGs, patient diaries, etc will be monitored by monitor. The monitor checks that all relevant source data have been properly transcribed to the CRF.

3.3 Data Corrections

• If the monitor finds errors in the CRF entries or source data that require correction, additions or deletions, these must be clarified with the investigator or an authorised delegate at the trial site. The monitor is responsible for instructing the investigator or delegates in the correct way of performing corrections according to GCP.
• Entries/corrections on the CRF may only be made by the investigator or an authorised staff member at the trial site. The authorisation must be documented (authorized signatory log)
• A single line must be drawn through the original entry (must still be legible)
• The correct entry is written next to it
• The correction/addition must be initialed and dated by the investigator or the authorised member of the trial site staff
• If the reason for the correction is not obvious based on the documentation available, a reason must be given by investigator or trial site staff.

3.4 Queries

Unclear entries detected by data management are queried. These queries can be listed and taken to the regular monitoring visits, sent by post/fax to the trial site or marked in the e-CRF, respectively. Monitors must have a list of open queries for each trial site. Queries must be answered in writing by the investigator or an authorized staff member (authorized signatory log).

3.5 Drug Accountability

In order to ensure the correct handling of medication during clinical trials and to supervise the whereabouts of the trial medication, the monitor verifies the correctness and integrity of the data in the ISF provided by the trial site and/or pharmacy. Reception and return of trial medication by the trial site must be confirmed in writing by the investigator or an authorized person (e.g. pharmacist). This must be checked by the monitor. CRA will also check storage conditions are acceptable and supplies are sufficient.

3.6 Notification of Serious Breach

Minor deviations from clinical trial protocols and GCP occur commonly in clinical trials. The majority of these instances are technical deviations that do not result in harm to the trial subjects or significantly affect the scientific value of the reported results of the trial. These cases should be documented e.g. in the case report form for the trial or trial master file, in order for appropriate corrective and preventative actions to be taken.

In addition, these deviations should be included and considered when the clinical study report is produced, as they may have an impact on the analysis of the data.

However, not every deviation from the protocol needs to be reported as a serious breach.

What needs to be reported?

• Any serious breach of:

1. the conditions and principles of good clinical practice in connection with that trial or
2. the protocol relating to that trial.

• For the purposes of this regulation, a “serious breach” is a breach which is likely to effect to a significant degree:

1. the safety or physical or mental integrity of the subjects of the trial or
2. the scientific value of the trial.

The judgment on whether a breach is likely to have a significant impact on the scientific value of the trial depends on a variety of factors e.g. the design of the trial, the type and extent of the data affected by the breach, the overall contribution of the data to key analysis parameters, the impact of excluding the data from the analysis etc.

3.6.1 Examples illustrating breaches classified as serious

• A breach of GCP or the protocol leading to the death, hospitalization or permanent disability of a trial subject. Please note, not every serious adverse event (SAE) or  suspected unexpected serious adverse reaction (SUSAR) would routinely be classified as a serious breach, but SAEs/SUSARs resulting from a breach of the conditions and principles of GCP or a breach of the protocol may constitute a serious breach.
• Proof of fraud relating to clinical trial records or data, if the fraud is likely to have a significant impact on the integrity of trial subjects or the scientific value of the data.
• Persistent or systematic non-compliance with GCP or the protocol has a significant impact on the integrity of trial subjects or on the scientific value of the trial. For example, widespread and uncontrolled use of protocol waivers affects eligibility criteria, which leads to harm to trial subjects or has a significant impact on the scientific value of the trial. Another example would be an investigator repeatedly failing to reduce or stop the dose of an IMP in response to a trigger (e.g. abnormal laboratory results) defined in the protocol.
• Failure to follow protocol-specific instructions about investigational medicinal product(s) such that trial subjects are put at significant risk or the scientific value of the trial is compromised.
• Failure to report adverse events, serious adverse events or SUSARs in accordance with the regulatory requirements.

3.7 Documentation of the Monitoring Visit

A detailed monitoring report should be prepared shortly after every visit to document the status at the site at the time of the monitoring visit (subject status, informed consent forms, protocol deviations, problems/difficulties, open questions, trial materials needed etc.), and the activities of the monitor at the trial site.

Review and approval of monitoring reports are done by the person responsible designated for each clinical trial. To ensure that any necessary measures are taken, the report must be given to the person responsible for the trial.

In critical cases, the findings of a monitoring visit must be passed on to the person responsible before finalizing the monitoring report.

The Investigator will be informed in writing of any problem(s) that were identified during the monitoring visit. If there is evidence of systematic failure to comply with GCP retraining will be given and management informed.

The monitoring reports should reflect the course of the clinical trial and, as original documents, must be archived in the Trial Master File (TMF).

Any deficiencies recorded in the monitoring report, future strategies for avoidance, problems and their solutions, and any outstanding points to be dealt with at the trial site within a defined period of time should be set out in a follow-up letter to the trial site shortly after the monitoring visit.

3.8 Status Updates between Monitoring Visits

Depending on the agreement, the status at the trial site should be regularly inquired by telephone and updated in writing. At the minimum, the following points should be discussed by telephone:

• Subject status
• Serious adverse events
• Changes in staff (changes in responsibilities)
• Problems/questions/difficulties
• Telephone calls should be documented.