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ICH E6 R3 Draft Guidelines are Transformative. Is your Quality Management Strategy Ready?

By Gaiety Manchanda, MSc, Associate Director of Quality Services


The long-anticipated draft efficacy guidelines of Good Clinical Practice (GCP) E6 (R3) brings transformative opportunity for the Quality community globally. This guideline has an evolved approach ensuring patient centricity, which is a much-needed addition to clinical trial regulatory guidelines. Additionally, it allows for enhanced quality and efficiency to overcome the evolving challenges of integrating technology into clinical trial design. R3 is a tailored, thoughtful approach to clinical trial types and public health emergencies such as the recent COVID-19 pandemic and covers a scope far greater than quality. Discussed in this blog are some of the key changes in the draft guideline as they apply to quality and quality strategy, to perhaps help guide our readers on how our quality community can input their feedback on this guideline draft.

E3 is a rewrite of E2 with clarity in different areas to cope up with the changing needs and requirements. Multiple terms have been added in the clinical trial ecosystem, such as:

· Data acquisition tool

· Metadata

· Service provider

This blog only lists few proposed changes to the guideline that may trigger some further changes.

Missing Components in E6(R2) are now covered in E6(R3)

Designing Proactive Quality into the Clinical Trial

Quality Management (QM) had been weighed heavily within R3. If all QM points remain unchanged when E3 is finalized, implementation of Critical to Quality (CTQ) factors will be unequivocally required with direct reference from ICH E8(R1). “Quality by Design (QbD) or “Designer Quality” should trigger the inclusion of CTQs at clinical trial design phase. Through the draft guideline the focus is really on CTQs and criticality of data. So, what would be covered under “critical “to quality factors for compliant research? Critical aspects such as the below should be included with a through justified process:

· Design

· Equipment

· System

· Process

· Procedures

· Endpoints

· Data

There are multiple ways of approaching this which are not explicitly covered in the revision. Sponsors and Stakeholders will need to thoroughly assess their systems to ensure the guidelines are adopted efficiently.

A Paradigm Shift to Risk Management Guidelines

Risk Management will fall under the umbrella of Quality Management (QM). First introduced within ICH-GCP E6 (R2), R3 clarifies the importance of risk mitigation strategies which should naturally be proportionate to the importance of data being collected. The risk management was not clearly directed within R2 or as it was not associated with the trial participant safety and data reliability e.g., risks that are beyond the standard medical of care. With the precision of the upcoming R3, guidelines take a focused approach when relating risk mitigation strategies to safety; a paradigm shift when it comes to participant’s care.

This is also directly related to the protocol and trial documentation design that should provide clear, concise, and operationally feasible execution of the trial in line with the guideline’s principles. Not only the QM processes, but the Quality Control (QC) also holds an important part in this guideline that is now required to be applied to each stage of data handling to ensure the data is reliable.

Data management and monitoring are the key processes that requires QC to be well netted in the decentralised, risk-based monitoring approach to be able to display CTQs. There are multiple ways of achieving this which are not specifically included in the guideline, but the stakeholders need to get the checkpoints and documentation right.

Data Governance Transformation

Data Governance is now joint processing by Investigator and sponsor. This is extracted from ICH E9 and E8(R1) to R3 with explanation on the requirements of processes. This is all in efforts to ensure critical elements such as the below are managed appropriately:

· Data Protection and Privacy

· Management of Computer Systems & Software

· Safeguarding essential elements of clinical trials

o (e.g., dose escalation

o randomisation

o blinding)

· Supporting key decision making, e.g., changes in clinical trial design.

Safeguarding blinding in a clinical trial is to be taken seriously and potential unblinding should be part of risk assessment of a blinded trial. Relevant metadata and audit trails from the computerised systems should be maintained for all critical data points. The sponsor will also be responsible for reviewing that the systems used by investigator/institution (e.g., electronic health records) and for clinical trial data collection are “fit to purpose” in the context of trial.

(Curious on how to future proof your CQA Strategies? Check out two posts from our Computer Systems expert Mason Cox here and here)

The investigators/institutions are also responsible for ensuring the expectations are addressed while deploying the computerised systems. Although the processes existed in different guidelines and regulations, these are now included more formally in E3 with ownership authority to each stakeholder participating in development, assessment, usage and reviewing the systems and data.

While the guideline does focus on patient centricity it also brings flexibility for the participating investigators in their qualifications, trainings etc. e.g., the trial specific delegation documentation is not required where the clinical trial activities are performed in routine clinical care, trial related trainings are to be provided to the site staff assisting in clinical trial corresponding to the necessity of fulfilling trial related delegated activities. It is also proposed that the long Investigator’s Brochures should be replaced with basic product information when the product has a marketing authorisation. Clinical trials to be described in a “simple,” clear, concise, and operationally feasible protocols.

A Holistic Approach to Training Quality Professionals

Training on the updated guideline should be taken by stakeholders at all levels and the industry should ensure that the quality assurance function implements these changes in their organisations (sponsor, contract research organisations, investigator sites, independent review boards/institutional ethics committee) in a holistic way and update the relevant processes, procedures as these guidelines get finalised. This is a big “simple critical” change that should be welcomed to ensure that as an industry “we” walk towards the need of the time, prioritise participant safety, make treatments available for the existing and new diseases by use of custom-tailored quality strategies, factors for data reliability to know what non-negotiable to achieve that aim.


The latest draft guidelines to GCP ICH E6 R3 is a transformative approach to quality within Clinical Trial design. Taking a more proactive approach to quality by building it into the design of the trial will save sponsors time and budget by ensuring quality is built in. Risking factors, improved handling of data and management of data governance will all result in overall less risk to the trial but resulting in better patient management and outcomes.

Gaiety Manchanda MSc, is a true global expert in several GxP areas including GCP, GcLP and GLP Quality. With 15 years of direct quality experience in industry, Gaiety has spent the majority of her career in Quality. She moved through increasing levels of seniority within clinical quality assurance with multiple domains of experiences in Quality management systems, Quality strategies and has an extensive experience auditing in global locations including: the United States, Canada, United Kingdom, Eastern and Western Europe, The Middle East, China, Japan, South Korea, Vietnam, the Philippines, Thailand, India, Australia, and New Zealand. Her vast experience enables a uniquely global perspective in bringing quality best practices to our clients.


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