The International Conference on Harmonisation’s (ICH) Guideline for Good Clinical Practice (GCP; document E6) is currently being revised. The FDA published the new version, which will be called E6 (R2), as a draft document in the Federal Register in June 2015. The draft contains numerous revisions that address changes in the scale, complexity, and cost of clinical trials since the previous version was adopted. Since clinical researchers have access to new technology and risk management processes that may increase efficiency and focus on relevant clinical trial activities, E6 is being amended to encourage the implementation of improved and more efficient approaches to clinical trial design, conduct, oversight, recording, and reporting, while ensuring that human subject protection and data integrity are maintained. In addition, the update includes changes to clarify standards on electronic records and essential documents. Ultimately, the new document is designed to help clinical researchers protect human subjects, maintain data quality and integrity, and properly document trial results. This article will highlight the key changes that affect research practitioners. These revisions are expected to be reviewed and accepted within ICH and then incorporated into the E6 document by the end of 2016.

SECTION 1: GLOSSARY

Section 1 (Glossary) includes the addition of new definitions or enhancements to existing definitions. One key enhancement is found in the definition in a certified copy of a case report form (1.11). This enhanced definition states: “A paper or electronic copy of the original record that has been verified (e.g., by a dated signature) or has been generated through a validated process to produce an exact copy having all of the same attributes and information as the original.” This enhancement helps clarify how to determine the validity and acceptability of copies of all trial-related records, including source documents.

The definition of monitoring (1.38) has been broadened to include the monitoring plan, which is defined as “A description of the methods, responsibilities, and requirements for monitoring the trial.” The updated guideline does not require the monitoring plan to be a standalone document, but makes an expectation that a formal plan exists. In addition, the monitoring report (1.39) definition has been expanded to include “Outcomes of any centralized monitoring should also be reported.” Many sponsors now include centralized monitoring as part of their overall monitoring processes; however, since this monitoring does not occur during a formal onsite monitoring visit, it may not be adequately documented. The expanded definition will ensure that sponsors create a report to show the centralized monitoring that was performed.

The definition of unexpected adverse drug reaction (1.60) now includes a new definition titled “validation of computerized systems” (1.60.1). However, there does not seem to be an obvious relationship between the definition of adverse drug reactions and this new definition—“A process of establishing and documenting that the specified requirements of a computerized system can be consistently fulfilled. Validation should ensure accuracy, reliability, and consistent intended performance, from design until decommissioning of the system or transition to a new system.” A more logical step would be to make this new computer validation definition 1.61 and then renumber the last two definitions in the Glossary (vulnerable subjects and well-being) to 1.62 and 1.63, respectively, which may be done when the final document is released.

SECTION 2: PRINCIPLES OF ICH GCP

The draft also slightly revises the Principles of ICH GCP (Section 2). In section 2.10, the statement “All clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation, and verification” has been enhanced to also state “This principle applies to all records (paper or electronic) referenced in this guideline.”

The draft makes no proposed changes to the Section 3, Institutional Review Board/Independent Ethics Committee.

SECTION 4: INVESTIGATORS

Several additions are proposed to the Investigator section (section 4). In Adequate Resources (section 4.2), two new statements are proposed. First, section 4.2.5 is updated to state: “The investigator is responsible for supervising any individual or party to whom the investigator delegates study tasks conducted at the trial site.” Second, section 4.2.6 is updated to state: “If the investigator/institution retains the services of any party to perform study tasks, they should ensure this party is qualified to perform those study tasks and should implement procedures to ensure the integrity of the study tasks performed and any data generated.” These qualification and supervision responsibilities were not explicitly stated in the previous version, but clinical trial sponsors expected investigators to follow these guidelines. Notably, the updated statements now reflect FDA’s well-established guidance on the investigator’s supervisory responsibilities.

In section 4.9, Records and Reports, a new introductory statement (4.9.0) has been added that states “The investigator should maintain adequate and accurate source documents and trial records that include all pertinent observations on each of the site’s trial subjects. Source data should be attributable, legible, contemporaneous, original, accurate, and complete. Changes to source data should be traceable, should not obscure the original entry, and should be explained if necessary (e.g., via an audit trail).” The adoption of the ALCOA (attributable, legible, contemporaneous, original, and accurate) acronym for creating adequate documentation signifies FDA’s influence on the ICH GCP revision.

SECTION 5: SPONSORS

Section 5, Sponsors, contains substantial changes and additions. The draft includes a major new section 5.0 (Quality Management), in which the concepts of quality management, with an emphasis on risk management, are integrated into the sponsor’s responsibilities. Although risk management processes are well known in the medical products industry, they have not been widely applied to the planning and implementation of clinical trials. The update will require clinical trials sponsors to begin acquiring the necessary training and resources to establish these principles. Two helpful general resources are ICH Q9, Quality Risk Management, which is a high-level overview of risk management principles, and ISO 14971, Application of Risk Management to Medical Devices, a global safety standard applicable to all stages in the life cycle of a medical device, including its early development. While both these documents are tailored toward manufacturing risk management, they may present useful information applicable to clinical trial planning, as well. Table 1 lists the full text of the proposed quality management section. 

Section 5.2, Contract Research Organization (CRO), includes two proposed changes that require sponsors to take a more active role in overseeing their CROs. Section 5.2.1 has been enhanced with the following statement:  “The sponsor should ensure oversight of any trial-related duties and functions carried out on its behalf.” Section 5.2.2 has been enhanced with the following statement: “The sponsor should document approval of any subcontracting of trial-related duties and functions by a CRO.” This is particularly relevant to small and start-up sponsors that rely heavily on CROs for managing most or all trial-related activities. The revisions state that sponsors may not abdicate this responsibility and must take a more active role in their oversight of their CROs.

Section 5.5 (Trial Management, Data Handling, and Record Keeping) also includes various changes. Section 5.5.3 (b) is modified to clarify expectations for standard operating procedures (SOPs) for electronic data handling and systems. The proposed language states “The SOPs should cover system setup, installation, and use. The SOPs should describe system validation and functionality testing, data collection and handling, system maintenance, system security measures, change control, data backup, recovery, contingency planning, and decommissioning. The responsibilities of the sponsor, investigator, and other parties with respect to the use of these computerized systems should be clear, and the users should be provided with training in the use of the systems.” The draft also includes a new statement 5.5.3 (h), which states that sponsors are expected to “Ensure the integrity of the data including any data that describe the context, content, and structure of the data.” This addition is particularly important when making changes to the computerized systems, such as software upgrades or migration of data.

Revisions to the section on monitoring (5.18) reflect a stronger reliance on risk-based monitoring. The revisions incorporate the elements from the FDA’s recent guidance on risk-based monitoring. These revisions are noted in section 5.18.3 (Extent and Nature of Monitoring) and include the following enhancements: “The sponsor should develop a systematic, prioritized, risk-based approach to monitoring clinical trials. The flexibility in the extent and nature of monitoring described in this section is intended to permit varied approaches that improve the effectiveness and efficiency of monitoring. A combination of on-site and centralized monitoring activities may be appropriate. The sponsor should document the rationale for the chosen monitoring strategy (e.g., in the monitoring plan).”

In addition, the ICH revisions highlight the use of centralized monitoring as an important strategy to complement and reduce the extent and/or frequency of onsite monitoring. Examples provided are:

• Routine review of submitted data.
• Identification of missing data, inconsistent data, data outliers, or unexpected lack of variability and protocol deviations that may be indicative of systematic or significant errors in data collection and reporting at a site or across sites, or may be indicative of potential data manipulation or data integrity problems.
• Use of statistical analyses to identify data trends such as the range and consistency of data within and across sites.
• Analysis of site characteristics and performance metrics.
• Selection of sites and/or processes for targeted on-site monitoring.

Section 5.18.6 (Monitoring Report) includes a new section (e) that states “Monitoring results should be provided to the sponsor (including appropriate management and staff responsible for trial and site oversight) in a timely manner for review and follow-up as indicated. Results of monitoring activities should be documented in sufficient detail to allow verification of compliance with the monitoring plan.”

The draft also proposed a new section 5.18.7 (Monitoring Plan) that states: “The sponsor should develop a monitoring plan that is tailored to the specific human subject protection and data integrity risks of the trial. The plan should describe the monitoring strategy, the monitoring responsibilities of all the parties involved, the various monitoring methods to be used, and the rationale for their use. The plan should also emphasize the monitoring of critical data and processes. Particular attention should be given to those aspects that are not routine clinical practice and that require additional training. The monitoring plan should reference the applicable policies and procedures.”

Section 5.20 (Noncompliance) includes an enhancement that reflects regulatory authority expectations that sponsors will attempt to identify the causes of non-compliance in a robust way and implement effective corrective and preventive strategies. The new section (5.20.1) states: “When significant noncompliance is discovered, the sponsor should perform a root cause analysis and implement appropriate corrective and preventive actions. If required by applicable law or regulation, the sponsor should inform the regulatory authority(ies) when the noncompliance is a serious breach of the trial protocol or GCP.”

SECTION 8: INTRODUCTION

The last revision adds to section 8.1 (Introduction) the following enhancements: “The sponsor and investigator/institution should maintain a record of the location(s) of their respective essential documents. The storage system (irrespective of the media used) should provide for document identification, search, and retrieval. Depending on the activities being carried out, individual trials may require additional documents not specifically mentioned in the essential document list. The sponsor and/or investigator/institution should include these as part of the trial master file. The sponsor should ensure that the investigator has control of and continuous access to the CRF data reported to the sponsor. The sponsor should not have exclusive control of those data. When a copy is used to replace an original document, the copy should fulfill the requirements for certified copies. The investigator/institution should have control of all essential documents and records generated by the investigator/institution before, during, and after the trial.”

By Anna DeMarinis, MA, CQA(ASQ), MTA(ASCP)SBB

This article was reprinted from Research Practitioner, Volume 17, Number 4, July-August 2016.