The MHRA published the GXP Data Integrity Guidance in March 2018 (see post). This was welcomed by industry and has been discussed at many stakeholder events since. As part of our engagement with stakeholders, we welcome feedback on guidance issued and the Data Integrity (DI) guidance is no exception. As such, we will be issuing a series of GXP blog posts to assist further on the reflections received since the issuance of the guidance.
This series of posts starts with the Good Clinical Practice (GCP) perspective. We have been made aware of some clarification needed in the interpretation and implementation of the GXP DI guidance in the clinical trial setting, which we hope to clarify via this post.
Audit Trail Review
The guidance describes the need for a documented audit trail review, where the need for and extent of such evaluation is identified in the trial risk assessment, performed prior to the trial commencing. This could include evaluation of data points associated with critical/complex trial processes, in other words, where the trial risks are. This has led many to question whether this means that sponsors, or indeed Clinical Research Organisations (CROs) working on behalf of sponsors, need to develop a generic audit trail review Standard Operating Procedure (SOP) that covers this process, that is, an SOP not specific to a particular clinical trial as part of their quality system. To answer this question, we would refer organisations back to the statement that the need for a review of an audit trail should be determined by a risk assessment based on the requirements of the trial, taking into account the systems, procedures and controls in place to be used in the trial. Therefore, to have a generic SOP would probably not add any benefit to this process and is not mandated by the guidance or expected by GCP inspectors.
It should be noted that the audit trail review referred to in the DI guidance refers to those data collection activities that have a formal computer-generated audit trail. Other ways of demonstrating data integrity and reconstruction of the life cycle of a record are of course possible where other ways of collecting data are used.
Conducting a trial risk assessment upfront has long been recommended by the MHRA GCP inspectors as a way of identifying and mitigating all risks associated with your clinical trial (see Risk Adaptation post), and this is supported by the ICH E6 (R2) Addendum. This risk assessment should address the most appropriate approach to demonstrating the integrity of the data required by the clinical trial protocol. That is, the risk assessment for data integrity can be incorporated into the standard trial risk assessment and does not necessitate a separate document/duplicate of information already contained within the overall trial risk assessment.
Recording of Patient Data
We have been asked what the practical implications of the DI guidance are in the clinical setting, in particular in relation to recording of patient data, and the need for a second person to verify, for example, vital signs from the recording instrument, as has been the interpretation by some organisations. Section 5.2 of the DI guidance states that ‘recording by the second person should be contemporaneous with the task being performed, and the records should identify both the person performing the task and the person completing the record’. From the clinical and GCP perspective it is of course common practice for one person, as part of standard medical care, to take readings from instruments not equipped with a computerised data system or recording device, such as a thermometer. In such standard clinical situations occurring in clinical trials, this can absolutely be the same person performing the task and completing the clinical trial record. A second person would only be needed if, from a clinical perspective, it is not practical for one person to both perform the clinical tasks and record the data. There is absolutely no expectation from the DI guidance to have 2 people responsible for this.
Amount and Resolution of Data to be Collected
We have been asked, in the GCP context, exactly what it means to collect data that ‘allows the full reconstruction of activities, the amount and the resolution (degree of detail) of data to be collected’, as per section 6.7 of the DI guidance. Concern has been raised that this may mean organisations (whether sponsor/CRO/contracted organisation) should be developing a stand-alone SOP for determining the amount and resolution of data to be collected.
Determining the amount and resolution of the data to be collected is an integral part of clinical trial quality/data management as defined by ICH E6(R2). The precision, accuracy and timing of clinical measurements are determined by the authorised clinical trial protocol and are commonly addressed and documented as part of an organisation’s overall quality management planning, rather than specifically in relation to any ‘separate’ DI considerations. Therefore, it is up to organisations to determine the best way to approach this as per their quality system, and there is no statutory requirement to have a stand-alone SOP.
Overall, the important message of this post is that the GXP DI Guidance introduces no new statutory requirements for clinical trials, or specific requirements for mandatory SOPs. As with all relevant guidance there is an expectation that this is followed (as per ‘The investigator and sponsor shall consider all relevant guidance with respect to commencing and conducting a clinical trial’ Schedule 1, Part 2(8): UK Clinical Trials Regulations 2004, as amended).
How the guidance is implemented, however, should be determined by an organisation’s existing quality system, the need for additional procedures determined by the requirements of an individual trial or scope of work, and should not require duplication of existing SOPs or ways of working simply to fulfil the perceived needs of the DI guidance.
If you have specific queries regarding this you can contact the Clinical Trial Helpline (email@example.com) or, to discuss with fellow stakeholders how they are approaching this area, the MHRA GCP Forum is a good informal environment to use.
We would like to thank the Association of Clinical Research Organisations (ACRO) for their feedback and input into this discussion from the CROs that they represent.
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