CT SOP version no 2.0

Main changes from CT SOP version no 1.0: Adapted to ICH GCP R3 wording. Added ICH E19 "A Selective Approach to Safety Data Collection in Specific Late-stage Pre-approval or Post-approval Clinical Trials."  

Main changes from LM SOP No. 2.02. version nr. 3.1. Adapted to the wording of the clinical trial regulation no 536/2014 and to ”Risk proportionate approaches in clinical trials”.

Sponsor has an overall responsibility to implement a system to ensure quality in all phases of the trial according to this SOP. Sponsor should ensure all aspects of the trial are feasible. Unnecessary complexity should be avoided. The protocol, the data acquisition tool, the monitoring plan and other trial documents should be clear, concise and consistent. These tasks is delegated to the coordinating investigator.

The sponsor may transfer any or all of the sponsor's trial-related duties and functions to a service provider such as a Contract Research Organisation (CRO), but the ultimate responsibility for the quality and integrity of the trial data always resides with the sponsor. The sponsor should ensure oversight of any trial-related duties and functions carried out on its behalf. Transfer of duties shall be specified in a written agreement.

Before study start

Quality of a clinical trial is considered as fitness for purpose.

A well written protocol is the first step to ensure the quality of the trial, see Protocol - SOP 1.2.a.

The protocol should consider all processes and critical data to ensure the well-being of the trial participant and the reliability of the study results. Study specific procedures may also be required to complement the protocol e.g. on how to handle biological samples.

Next step of the quality management is to ensure an adequate data acquisition tool (DAT) is available for the study. A paper-based tool is acceptable, but not recommended. See data acquisition tools for DATs (electronic Case Record Form). For single centre studies, the institution might have other DATs available.

Risk proportionate approaches in clinical trials provides recommendations especially concerning safety reporting, investigational medicinal product (IMP) traceability and accountability, monitoring and trial documentation. In short, the following adaptation could be considered based on a risk assessment included in the protocol:

• Selective recording and reporting of adverse events and/or adaptation to immediate reporting from the investigator to the sponsor for certain serious adverse events. See also A Selective Approach to Safety Data Collection in Specific Late-stage Pre-approval or Post-approval Clinical Trials
• Reduced accountability records for IMPs used as described in the Summary of product characteristics (SmPC)
• Reduced monitoring (see below)
• The content of the trial master file and Investigator’s site file will follow the adaptations made for the trial. Worth noting is that the clinical study report may be absent as it is replaced by a medical journal publication (reporting of results in CTIS still applies), temperature monitoring and labelling may not be necessary, laboratory accreditation certificates and reference ranges may be omitted if the analyses do not provide critical information to the reliability of the trial results

A risk assessment should be performed by the coordinating investigator and should be conducted before the trial is initiated and thereafter on a regular basis throughout the trial. It is recommended that an interdisciplinary group of involved study personnel and support functions participate in the risk assessment. The focus should be on risks that go beyond those associated with usual medical care. 

The risk assessment should consider whether the clinical trial is a low-intervention trial, the objective and methodology of the trial and the degree of deviation of the intervention from normal clinical practice. A useful template to be used for risk assessment is Risk Assessment . This template also includes an Organisational Overview. Risks associated with sites should be gathered when evaluating the sites and should be listed in the Risk Assessment.

The purpose of the risk assessment is to identify specific processes critical to ensure trial subject’s protection and the integrity of the data to be collected in the trial. The risk assessment should also include an evaluation of the following parameters:

• Likelihood
• Consequence
• Risk for not detecting

The parameters should be graded. Further, the assessment should also include a consideration whether the risk is acceptable or not, and if acceptable; an assessment of the need for threshold values, e.g. how much deviation/how many deviations can be accepted before certain measures or actions should be taken.

As an outcome of the risk assessment, the coordinating investigator will decide upon different solutions and actions to be performed and by whom, to prevent or reduce the risk for events and deviations to occur. The risk mitigation strategies should be proportionate to the importance of the data being collected and the risks to trial participant safety and the reliability of trial results.

Before the study is initiated, a Monitoring Plan for the study will be written. This should consider the risk assessment already done and mitigate risks identified, which can effectively be revealed and corrected by monitoring. Examples of risks that can be mitigated by monitoring is lack of adherence to protocol, inadequate consenting procedure, deviation in collection of primary and secondary endpoints or safety data, missing essential and required study documents and inappropriate facilities and equipment.

Recruitment and delivery phase

A regular review of the risk assessment is required. This can be done annually, e.g. at the time for submitting the annual report through the Clinical Trial Information System (CTIS). A more frequent review may be required. The regular review should also include a check that previous solutions and actions agreed upon are completed accordingly. Any changes in the risks may influence e.g. the monitoring plan, the protocol or study conduct process.

Decisions related to the trial should be appropriately assessed for their impact on participant’s rights, safety and well-being and the reliability of trial results. If the decisions are taken in between general risk assessments, it is highly recommended to archive those decisions together with the risk assessments.

All quality management activities should be documented and communicated to the concerned parties.

Close-out phase

The quality management implemented for the trial together with important deviations should be taken into consideration when publishing the trial results.  

• Risk Assessment - Template
• Monitoring Plan - Template