IGMPI is conferred with ASSOCHAM Services Excellence Award 2017: Our Directors Mr Syed S. Abbas & Mrs Rafat Abedi, Chief Advisor Dr Mahesh Gupta, Advisor Mr Amitabh Srivastava are being honoured by the Chief Guest & Honorable Member of Parliament Dr. Udit Raj

 Recipient of QCI - D.L. Shah National Quality Award

Recipient of QCI - D.L. Shah National Quality Award

Targeting to fill up the gap between the existing and accessible knowledge

Targeting to fill up the gap between the existing and accessible knowledge

 

ICH-GCP E6 R2

ICH-GCP E6 R2

This is the revision of original ICH-GCP E6 Guidelines on Good Clinical Practice.

ICH now stands for International Council for Harmonization of technical requirement for human use. This was formerly known as International Conference for harmonization of technical requirements for human use. It is made up because founding regulatory members which are the the European commission, the FDA,Ministry of Health, Labor Welfare (MHLW), Japan. There are also standing regulatory members like Health Canada and Swiss Medic. Several industry members that are part of this group and observers which includes World Health Organization (WHO), the International Federal of Pharmaceuticals, Manufacturer’s Association,The Council forInternational Organization of Medical Sciences (CIOMS) and various organization from different countries. Involvement of all these regulatory agencies allows us to implement revised ICH guidelines across the globe. With regard to the changes what has happened is that the pace having picked up in clinical research and the use of technology , the previous guidelines ICH E6 had to be adjusted to keep up with the current changes. When the ICH group realized this they put together a process for revision to the E6 guidelines. If we look at the process what has happened was in 2014 an expert working group was particularly set up to revise the E6 guidelines. Good Clinical Practice Guidelines was assigned to this group. The whole process was divided in to the steps:

Step 1: this involved having a draft technical document ready

Step 2:  this involved refined document ready and to issue the draft guideline. This step was completed by June 2015.

Step 3:  this involved expert discussion which was finalized in Lisbon in June 2016 which lead to Expert draft guidelines. These guidelines were up for comments and review.

Step 4: the final guidelines were ready in November 2016.

Currently, what we see is the guidelines finalized in Step 4 in November 2016. This is the first revision since the guidelines were finalized in 1996. The purpose of this guide is to enable more innovative approaches to trial design, management, oversight, conduct, documentation and reporting. In addition, standard for electronic records and essential documents have also been updated and clarified. While these main points were maintained throughout, the human subject protection and reliable quality data are of primary importance.

While going through E6 R2, the changes are integrated into sections of the original guidelines since it is referred to as the “Integrated Addendum”. It is published as the ‘Changes to the full text with insertions’. There are no deletions in earlier text, only additions are done. Changes have been made are applied to sections of the

  • Glossary
  • Principles of ICH-GCP
  • Investigator responsibilities
  • Sponsors’ responsibilities
  • Essential documents

Each of these sections was thoroughly reviewed and is presented as individual section updates.

Changes to Glossary

ICH has now added a definition of a certified copy where in case of paper records have to be verified by dated signature. An electronic record involves a certified copy generated by a validated process. The revised guidelines mentiona Monitoring Plan which is now mandatory for all applicants. The guideline also recommends Monitoring report which should be now original for both centralized and /or remote monitoring activities as well as on-site monitoring activities.

There should also be validation of computer systems employed in clinical trial management. This is achieved by establishing and documenting the specified requirements of a system from a design perspective and decommissioning of the system or transition to a new system. This is in keeping with the current FDA guidelines where the approach to validation should be based on risk assessment that takes into consideration the intended use of the system and the potential of the system to affect human subject protection and reliability of trial result.

Changes to the Principles of ICH-GCP

The principle in particular that this effect is the 13 principles of ICH GCP is 2.10. Principle 2.10 states that ‘all clinical trial information should be recorded, handled and stored in a way that allows it accurate recording in terms of interpretation and verification’. The addition to this is that this principle is now applicable to both paper and electronic records.

Changes to Investigator’s Responsibilities

Additions have been made to sections 4.2.5 and 4.2.6 which deals with adequate resources. The investigator is responsible for supervising individuals to whom study tasks have been delegated.

The investigator has to ensure that the service providers are qualified to perform assigned duties and procedures that are implemented to ensure integrity of tasks and data generated.

With regard to records and reports, ICH have finally documented what we have doing all along and added an addition to ithi. The traditional ALCOA which was put together by investigator now has an additional component and is known as ALCOAC , the ‘C’ being ‘complete’.

The new revised guidelines for ALCOAC which means that documentation should be attributable, legible, contemporaneous, original accurate, and complete. Complete being the addition to traditional ALCOA.

Changes to Sponsors’ Responsibilities

The guidelines have outlined the need for quality management systems. It specifies a risk based approach which includes:

  • Critical process and Data identification
  • Risk identification
  • Risk evaluation
  • Risk control
  • Risk communication
  • Risk review
  • Risk reporting

This picks up on a lot of GCP inspections that were conducted previously and with these processes in palace in the revised guidelines, it should allow us to have more robust quality management systems and fewer findings.

The guidelines also assigned sponsor oversight of CROs and other vendors as a responsibility. There has to be a documented approval of duties assigned to CROs or any other vendors. The trial management data handling and record keeping has been updated to include SOPs for computerized systems. These SOPs should discuss system set up, installation, and use. There should also be SOPs on system validation, functionality testing, data collection and handling, system maintenance , system security measures, change control, data backup, recovery, contingency plan and decommissioning. There should be SOPs on responsibilities of Sponsors, Investigators, and others when using computerized systems so that there should be clear understanding of how the system works. Training has to be provided to all users. The guideline also states that it is sponsors’ responsibilities to ensure integrity of data with any changes such transition to a new system or an upgrade to a current system.

The additions to monitoring have placed emphasis on risk based monitoring approach that is flexible but systematic. The guidelines states that Centralized or Remote monitoring should be utilized for routine review of data in order to:

  • Identify missing or inconsistent data or any outliners
  • To examine data trends
  • To review any potential data manipulation or data integrity concerns
  • To review to pick up and review any unexpected lack of variability. It gives us an overview of site and other performance metrics and the selection of site that should be targeted for on-site monitoring.

With this in mind the sites that are of higher risks could now be monitored more frequently to avoid any inconsistencies in data collection. With regard to monitoring report, there is requirement for both on-site and remote or centralized monitoring visits. These should be documented in adequate details to verify compliance with the monitoring plan. The reports have to be sent in a timely manner to the sponsor and copied to others responsible for oversight. The guideline also mentions following-up on issues that are indicated in the report and having these documented. The Monitoring plan is tailored to specific human subject protection and data integrity risks of the trial. It should describe the strategy, responsibilities, methods and rationale for monitoring of the study. There should be attention to critical data and processes and this should include training as well. This has now become an integral part of the monitoring plan of the new guidelines.

With regard to non-compliance, the guideline says that it is sponsor’s responsibilities to take prompt action, perform a root cause analysis and implement corrective and preventative actions (CAPA). If required by a local law or regulation, regulatory authorities has to be informed when it is a serious breach of protocol or GCP or if it significantly affects human subjects’ protection or trial results.

Changes to Essential Documents

Section 8.1 has added that sponsorand investigator or institution should maintain the record of the location where documents are stored. The storage system that is used should provide for document identification, search, have the correct document version and allow for retrieval. ICH-GCP recognizes that the default essential document list may be inadequate. So the sponsor and investigator must include essential files in Trial Master Files which are specific and relevant to the trial. The sponsor should ensure that the investigator has control of as well continuous access to CRF data that is reported to the sponsor. The sponsor should not have exclusive control of the data which how it was previously. Should a copy replace an original document, it should be a certified copy and documented as such. The investigator or institution has to retain control of all the essential documents they generate before, during and after the trial.

ICH-GCP is the cornerstone of clinical research, this new level of standards has been defined. The real test is the implementation given the pace at which research an ICH-GCP is moving, we can only owe benefit from this.

The new revision of guideline include computerized systems, routine monitoring as well as quality management system which can only serve to enhance both data integrity and patient safety. Let us go ahead in what we have been doing all the time which is:

Thinking Smart| Thinking GCP

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