What you need to know about the ICH GCP E6 (R2) Addendum

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The development of new Medicines to improve life is a long and sophisticated process involving many people and significant investments. The increased complexity of the new molecules and strict regulatory monitoring lead to the implementation of electronic data handling technologies in the clinical trials such as data capturing programs and other computerised systems. Moreover, to provide reliability of the new molecules, clinical tests need to be carried out on different population groups and that has led to the conducting of multi-site clinical trials at various locations.

The consequence of this complex process has led to the transferring of trial-related duties of the Research process to third-party companies. The outsourcing raised questions as to whether enough care is made to assess the risks of how a sponsor can monitor the process of a clinical research trial and how to ensure data integrity when using a computerised system in a clinical trial.

Multiple reports from GCP regulatory inspections around the world listed major problems related to the clinical study report, data management and inept monitoring activities.

Metrics and Results

In 2014 the European Medicine Agency (EMA) submitted a report summarising the findings of 398 GCP inspections carried out by the agency for the period of 2000-2012.



The EMA GCP Inspection report included investigator sites, sponsors, contract research organisations (CROs) and a few other sites related to clinical trials such as clinical and analytical labs. In most cases, Critical findings of the GCP inspections fall into three sub-categories which are:

  • Monitoring
  • Data management
  • Clinical study report (CSR)

Evaluation of the Major findings revel that most of them are in relation to:

  • Monitoring
  • Source Documentation
  • Data management

Most of the Critical and Major findings are concerning the monitoring, data management, and clinical trial documentation. The obligations for those results are assigned to inadequate quality control and decreased sponsor oversight. When categorised by type of site it becomes apparent that most major and critical findings are observed at Clinical Investigator, Sponsor, and CRO sites. Furthermore, the sponsor and the CRO accounts for nearly 43% of the total findings1.

The new ICH GCP E6 R2 regulations

To address the concerns from GCP regulatory inspections in June 2015, the ICH released an amended version of the international guidelines for GCP: ICH GCP E6 (R2). The new GCP draft represents the biggest revision of the international ICH GCP guidelines for over 20 years, and has the potential to fundamentally alter the way in which clinical research is managed (2). The EMA welcomed the R2 changes, stating that these new guidelines “will provide increased clarity and encourage implementation of improved and more efficient approaches to clinical trial design, conduct, oversight, recording, and reporting” (3). The new ICH GCP E6 (R2) Addendum introduced 26 new items covering three main areas of clinical research: data management, and sponsor and investigator responsibilities (see Table 1 below).


(Classification of the ICH GCP E6 (R2) Addendum

From the amended section of the new guidelines for GCP, it is apparent that the R2 Addendum is addressing the concerns of the GCP regulatory inspections over the years. The fundamental differences between the R1 and R2 version of the guidelines are in respect to sponsor/investigator responsibilities and risk-based monitoring. The new guidelines are likely to come into force in November 2016 and, once implemented, they will have a global impact on anyone involved in the clinical research process. However, what exactly will that mean to pharmaceutical companies, sponsors, CROs, research institutes and third party organisations? We will analyse in more detail the ways in which the Addendum will influence sponsors and investigators of clinical trials (4).



The investigator should assure that there is a suitable monitoring plan in place to supervise the different individuals engaged in the study. The various stages should also be tracked to ensure that adequate procedures are adopted to protect data integrity (see Table 1, amendment 4.2.5 and 4.2.6, page 15). In 2009, the FDA released guidelines that proposed measures for developing a monitoring plan. In 2011, the Medicines and Healthcare products Regulatory Agency (MHRA) also offered risk-based approaches for the management of clinical trials. Two sections concerning the investigator’s responsibilities, which are revised in the new ICH GCP regulations, are adequate resources, and records and reports.

Adequate Resources

The new duty of the principal investigator (PI) is to oversee the “individual or party to whom the investigator delegates study tasks conducted at the trial site” (5). Moreover, if the study work is outsourced to a third-party organisation, it is the obligation of the PI to “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” (5).

Records and Reports

The investigator must maintain records of the documents for critical processes and clear documented evidence of the PI’s oversight and involvement in the trial. Additionally, the PI needs to make certain that a clinical investigation is carried out according to the protocol, the investigational plan and applicable regulations. At the same time, the PI should establish a good communication infrastructure in order to monitor all activities in the study (6,7). The new GCP R2 goes even further by stating that the “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)” (5).


This section has experienced the largest modification, with a total of 16 new items added to the R2 version. The revised part offers a very detailed view of the sponsor’s responsibilities, including quality management, CRO, trial management, data handling, record keeping and noncompliance.

Quality Management

Another area with a significant change in the R2 Addendum is quality management. This section has eight contemporary items and it should be noted that what was once a recommendation for GCP has, as a direct result of this update, now become compulsory. The new guidelines state that “the sponsor should implement a system to manage quality throughout the design, conduct, recording, evaluation, reporting and archiving of clinical trials”, and that the sponsor “should focus on trial activities essential to ensuring human subject protection and the reliability of trial results” (5).

An additional important responsibility of the sponsor is to “ensure that all aspects of the trial are operationally feasible and should avoid unnecessary complexity, procedures and data collection” (5). The sponsor must also employ a risk-based approach to monitor the clinical trial. The GCP R2 Addendum outlines in detail how to identify, evaluate, control, review and report the risks when developing quality management systems (QMS).


Furthermore, the sponsor must “ensure oversight of any trial-related duties”, and “should document approval of any subcontracting of trial-related duties and functions by a CRO”. The further responsibilities of sponsors concerning the CRO will give them greater control and management over clinical trials.

Trial Management, Data Handling and Record Keeping

The control of information collected from data capturing programmes was also covered in great detail. Now, the obligation of the sponsor is to have written procedures in place for all electronic systems used in the trial. A standard operating procedure should be in place for “validation and functionality testing, data collection and handling, system maintenance, system security measures, change control, data backup, recovery, contingency planning and decommissioning” (5). The duties for the use and training of the electronic systems must also be clearly defined. Moreover, the integrity of the data needs to be kept when the electronic systems utilised in the study are updated with the new version of the software, and when data relocation takes place.


Noncompliance to the protocol, the GCP and the written procedure are the sponsor’s responsibility – in addition to that, when noncompliance occurs, the sponsor should perform a root cause analysis and implement a corrective and preventive action plan. Grave violations of the rules or protocolmust be reported immediately to the regulatory authorities.

For the Benefit of All

The ICH GCP E6 led the way by which clinical research was conducted over the years, but new technologies have rapidly shifted the process and, as a result, many trial-related duties were outsourced and automated. The ICH GCP managed to cope with the challenges of the clinical research, but it became evident that an updated version was needed to ensure the quality of the clinical study. A risk-based trial design will, undoubtedly, be essential to guarantee compliance with the amended regulations. The new riskbased QMS will lead to better monitoring of CROs, labs and other parties contracted in the clinical research process. Furthermore, the increased monitoring requirements concerning the sponsor and investigator will improve clinical research even further.

This article is taken from European Pharmaceutical Contractor November 2016, pages 14-17. © Samedan Ltd. A PDF copy of the article available here: epc-november-2016-p14-17. The current issue of EPC is available here: http://www.samedanltd.com/magazine/11.


1. Classification and analysis of the GCP inspection findings of GCP inspections conducted at the request of the CHMP, 1 December 2014
2. Wilsher C, ICH rewritten to reflect recent GCP inspection findings, RQA GCP Committee, August 2015
3. EMA, Submission of comments on ‘Guideline for good clinical practice E6 (R2)’ (EMA/CHMP/ ICH/135/1995), February 2016
4. Andrianov A, Wilder B and Proupín-Pérez M, ICH GCP goes risk based, October 2015
5. Integrated Addendum to ICH E6 (R1): Guideline for GCP E6 (R2), June 2015
6. Guidance for Industry: Investigator responsibilities – Protecting the rights, safety, and welfare of study subjects, October 2009
7. Risk-adapted approaches to the management of clinical trials of investigational medicinal products, MRC/DH/MHRA, October 2011


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