Ensuring ICH GCP Compliance in Semi-Virtual Clinical Trials Using Direct to Patient (O -Site) Research Nurses –Practical Considerations for Sponsors and CROs

Background

Number of trials involving “home care”, “direct to patient” or “O -Site” component has been steadily increasing over the past 20 years. The use of o -site Research Nurses has further increased with the move towards virtual (or site-less) trials. Although technology has driven the change to this more decentralised trial model, the use of o -site Research Nurses is a key component of the more patient centric model.Following the ICH E6 (R2) update, European Medicines Agency (EMA) Inspectorate Working Group (WG) issued two new posts on the Q&A website in Dec 2018 to further clarify how compliance with ICH E6 (R2) can be achieved and what steps must be taken when including an external O -Site Nursing provider (“Provider”) in any trial model.

Objectives

The intention is to identify di erent categories of actions and responsibilities from the Sponsor/ Contract Research Organisation (CRO), Investigator Site (“Site”) and Provider, to comply with ICH GCP E6 (R2).

Methods

The available guidance was reviewed and interpreted by the members of the Illingworth Quality Assurance department, with further input and clarification from the Medicines and Healthcare products Regulatory Agency (MHRA), EMA and Health Research Authority (HRA) was obtained. The results were categorised, and responsibilities assigned to each stakeholder (Sponsor/CRO, Site and Provider).

Conclusions

Sponsors/CROs looking to implement virtual and semi-virtual trial models to achieve patient centricity should ensure early engagement of both the Site and the Provider.

This will allow for open communication and appropriate, documented division of responsibilities across all parties, in turn ensuring regulatory compliance.

Essential Documents Approvals & Permissions

Study design, patient condition and drug indication support and justify o -site services. Protocol and other key documents (e.g. Lab Manual) identify procedures to be carried out o -site. Informed Consent Documentation reflective of o -site process including data sharing (with provider and partners e.g. courier).

Sponsor/CRO

Contracts & Agreements

IRB/IEC and Competent Authority approval of Protocol and ICD containing O -Site procedures.

Essential Documents Approvals & Permissions

Sponsor/CRO and Site agreement (e.g. mCTA) refers to the Provider and how delegation of Investigator duties will be documented.

Financial agreement between Sponsor and Provider.

Contracts & Agreements

PI review of Provider Nurse’s CV and acceptance of proposed resource.

Patient Safety Data Integrity Oversight

Risk Management Plan to include risks associated with o -site procedures.

Site

Written agreement confirming delegation of Investigator duties, as well as assurance of pre-engagement checks (training and experience) between the Site and Provider.

Other Institution requirements (e.g. insurance or indemnification arrangements).

Essential Documents

Develop instructions for the O -Site Nurses based on the protocol and relevant manuals. Due diligence checks on the Protocol, ICD and other documentation to ensure OSite procedures are adequately described.

Approvals & Permissions

Contracts & Agreements

Strict pre-engagement checks for each potential O -Site Nurse.

Review of source data worksheet template. Ensuring Provider has procedures for quality control and quality assurance (vendor qualification). Monitoring of data.

Regular communication with the -Site and Provider.

Patient Safety Data Integrity Oversight

Pre-visit handover between Site and O -Site nurse to ensure all relevant safety information is completed.

Provider

Financial agreement with the Sponsor, delegation agreement with the Investigator (may be per trial or a master agreement with individual scope of work). OR Tri-partite agreement including all stakeholders.

Pre-agreed timelines for return of completed worksheets.

Regular contact between O -Site Nurseand Site.

Patient Safety Data Integrity Oversight

Strict process to ensure protection of Subject Identifiable Information. Detailed country-specific due diligence to ensure compliance with data protection regulations.

Ensuring Life Support training of O -Site Nurses. Study specific risk assessment for o -site visits. Health and safety risk assessments for conducting osite visits.

“Meet the Patient” visits at Site prior to the first o -Site visit. StaySafe® platform for emergency notifications. Procedure for direct reporting of SAEs and other AEs of interest to the Site.

Quality control processes for data collected o -site. Timelines for data provision to sites. Secure storage of worksheets before return to Site.

O -Site Nurse attending Site Initiation Visit and periodically visiting the site. Regular communication between Site and Provider to schedule visits and exchange feedback.

Consideration of appropriate management of the GLP computerized system for data integrity

-Analysis of data integrity issues from FDA warning letters -

IsaoWatanabe: Shin Nippon Biomedical Laboratories, Ltd. Drug Safety Research Laboratories (SNBL DSR), Kagoshima, Japan

Co-author: Japan Society of Quality Assurance (JSQA), GLP Division, Study Group 3, Subgroup 2, Team A

Introduction

Globally, data integrity findings have been issued

Method

Step 1

Collected the FDA warning letters of data integrity issues related to computerized systems

Search on FDA website

Warning letters from April 2016 to August 2019

33warning letters from 9 countries in cGMP

Step 2 Categorized the data integrity issues of the FDA warning letters to the 5 phases of the data lifecycle

Result

Data integrity issues according to data lifecycle phase

What should be the focus point to improve data integrity at the GLP facilityinJapan?

Is staff training sufficient ?

Are effective controls in place for legacy systems ?

62 issues were categorized into the 5 phases

Discussion and Conclusion

In facilities where sufficient training on data integrity is not provided to staff, there is a concern that a lack of understanding will cause data integrity issues. Also, many facilities use legacy systems (insufficient functionality) and effective controls are required to ensure data integrity in such systems. Therefore, we adopted the methods described herein to consider appropriate management of the GLP computerized system focused on data integrity in Japan.

Purpose

To identify the focus point to improve data integrity based on categorizing according to the data lifecycle.

PhaseMain finding

*One issue may be classified into multiple phases

Inadequate control of computer clock or audit trail

Sharing a username and password

Storing on separate storage from the reported data

Multiple integrations or data deletion without just ification System administrator rights are assigned to staff with a direct interest in the data

Only the passing result was reported in the officia l record.

The extracted findings from the FDA warning letters were categorized into the 5 phases of data lifecycle. About 85% of data integrity issues extracted from FDA warning letters were categorized in the early phases of data lifecycle (generation and processing). Data integrity issues are likely to occur in the early phases of data lifecycle and may be the inspector's focus point. As a result, it is considered that the priority for GLP facilities to improve its response to data integrity should be focusing on the generation and processing phases of the data lifecycle. We plan to conduct activities to propose to Japan GLP facilities, measures for data integrity focusing on the generation and processing phases of the data lifecycle and to establish procedures for that purpose.

Certificates of Analysis can be manipulated or deleted

Unable to retrieve the data

Focus point of the data lifecycle to improve data integrity at the GLP facilityfrom this approach

(There were no applicable issues in this phase.)