"ICH E8 General Considerations for Clinical Trials”

Dansk selskab for GCP onsdag den 14 april 2021

LISBETH BREGNHØJ, LÆGEMIDDELINSPEKTØR, GCP, LÆGEMIDDELSTYRELSEN

Tak

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‒ Tak til E8 EWG medlemmer Carole Legare og Fergus Sweeney for lån af adskillige slides

Agenda

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E8 (R1) Work plan and current statusE6/E8 GCP renovation initiativeE8 (R1) Goals & ChallengesE8 (R1) Overview

– General Principles

– Promoting Quality by Design in clinical studies

– Critical to Quality Factors

– Drug development planning

– Study design considerations

– Study conduct & reporting

– Identifying CQFs

– Annexes

E6 (R3) Status

E8 (R1) Work plan

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• Original E8 document adopted in 1997

• ICH issued Reflection Paper on GCP Renovation in 2017

• E8 (R1) Expert Working Group formed in the same year

• E8 (R1) Draft published for public consultation from April to October 2019

• Adopting an ICH Harmonised Guideline planned for 2020

5

Stakeholder feedback on ICH E6 (R2) consultation

External Stakeholders’ Letter to EMA and ICH 31 Jan/26 Feb 2016– Academic stakeholders in 22 countries (5 organizations, 119 academic

researches)

Concerns• Need to improve focus on issues most critical for trial quality

• One size fits all approach is not suitable for different types of trials

• Academic stakeholders are not involved in the ICH processes

• 2016 ICH Meeting in Lisbon• Academic stakeholder representatives invited to meet with Management

Committee and ICH E6(R2) EWG representatives to discuss issues raised in their letter

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E8 is an integrative platform for other ICH guidelines (‘ICH E0’)

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ICH Reflection on GCP Renovation

• Step 1: Revision to ICH E8• Goal is to address broader concerns about the principles of study

design and planning for an appropriate level of data quality• Provides comprehensive cross-referencing to the family of ICH

guidance documents

• Step 2: Renovation of ICH E6 GCP• Goal is to address flexibility concerns with respect to a broader range of study

types and data sources• Retains the current focus on good clinical investigative site practices

Current status of E8

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E8 will not reach step 4 before June 2021, so development of training material has not been started yet.

E8 (R1) - Goals & Challenges

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• Promote fit-for-purpose clinical trials by:• Introducing ‘Quality by Design’ concept and identifying ‘Critical to

Quality’ factors • Upfront assessment of risks specific to development programme &

study design• Proportionate management of these risks and respective control

Facilitating a broad range of study designs and data sources

“This document focuses on designing quality into clinical studies, considering the diversity of clinical study designs and data sources used to support regulatory and other health policy decisions.”

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Reliable information

Decision making

General PrinciplesChapter 2

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• Protection of Study Participants• Health risks and confidentiality

• Scientific Approach• On development programme & study level. The development plan is considered to

cover the entire product lifecycle and include non-clinical, clinical, and post-approval studies.

• Iterative research process. The results of prior studies should inform the plan of later studies.

• Patient Voice• On objectives and design realisation• To improve feasibility & promote commitment

“The essence of clinical research is to ask important questions and answer them with appropriate studies”

Promoting high-quality studiesChapter 3

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• Introduces ‘Quality by Design’ concept to clinical research

• Suggests devising a specific set of factors critical to the quality of a given study (CQFs)

• Outlines approach to identifying and managing risks to CQFs“The likelihood that a clinical study will answer the research questions posed in a reliable manner, meaningful for decision makers and patients, while preventing important errors, can be dramatically improved through prospective attention to the design….of the …. protocol, procedures and associated operational plans.

Quality should rely on good design and its execution rather than overreliance on retrospective document checking, monitoring, auditing or inspection. These activities are an important part of a quality assurance process but are not sufficient to ensure quality of a clinical study.”

Critical to Quality Factors (CQFs)Chapter 3

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• Identifying attributes whose integrity is fundamental to study quality via:• Open dialogue, multiple stakeholders• Triage and focus on essential activities• Proactive implementation in protocol• Continuous review and risk-proportionate adaptations

Flexibility instead of one-size-fits-all strategy

Important bridge to be drawn to E6 – from what to how

Critical to Quality Factors (CQFs)Chapter 3

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– A basic set of factors relevant to ensuring study quality should be identified for each study. Emphasis should be given to those factors that stand out as critical to study quality.

– ..critical because, if their integrity were to be undermined …the reliability or ethics of decision-making would also be undermined.

– ..determine the risks that threaten their integrity, the probability and impact of those risks and to decide whether they can be accepted or should be mitigated.

– Where it is decided that risks should be mitigated, the necessary control processes should be put in place and communicated, and the necessary action taken to mitigate the risks

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‒ Perfection in every aspect ..is rarely achievable or .. only .. achieved by use of resources ..out of proportion to the benefit obtained. …study procedures should be proportionate to the risks inherent in the study and the importance of the information collected.

‒ Study designs should be operationally feasible and avoid unnecessary complexity and unnecessary data collection. Patient consultation early in the study design process contributes to these factors and would be likely to result in fewer protocol amendments. Protocols and case report forms/data collection methods should enable the study to be conducted as designed.

Drug development planningChapter 4

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• Considerations at the development programme level• From target product profiling through post-approval research• Main focus on clinical studies, combining step-wise evidence building with

flexibility in study planning• Special populations and study feasibility addressed as additionally important

issues

Types of clinical studiesChapter 4

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Elements of study designChapter 5

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• Key design aspects include:

• Study population

• Intervention

• Control group

• Response variable

• Bias reduction

• Statistical analysis

Data sourcesChapter 5

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• Broadly describes primary & secondary data generation/collection

• Primary data collection, refers to data collected for study purposes using processes that ensure a sufficient level of quality

• Secondary data use, refers to the use of data that were collected for other purposes and are not collected just for the study

• Acknowledges different data sources and respective methods and technologies used

• Highlights specific caveats and the importance of data standards

Study conduct & ReportingChapter 6

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• Study Conduct• Adequate protocol set-up, adherence and respective training• Data Management and appropriate/inappropriate (interim) access to study

data• Participant safety

• Safety monitoring, data collection and stopping rules• Role of Data Monitoring Committees

• Study Reporting• Reference to ICH E3• Promotes transparency and public access to study data

Identifying CQFsChapter 7

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• Example list of considerations to identify CQFs at the planning stage

• Non-exhaustive and of varying importance depending on the specific situation

• Evident «usual suspects», but an adaptive approach to devising CQFs is the core message

‘Living’ Annexes 1-3

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• Annex 1:• Plots research objectives and respective study examples along drug

development process• integrates chapters 4 (types of studies) & 5 (elements of study design

and data sources)• Annex 2:

• ICH E-Guideline family• Annex 3:

• Cross-referencing CQFs to other ICH documents as applicable

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E6 (R3) status

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Advanced principles draft…good news coming!Annex I in progress, drafting groups established on the sections deemed as needing most attention first

Principles

Annex –1

Annex-2

Step-1 / 2

Anticipated ApproachSimultaneous work on the principles AND Annex-1

Close coordination

Develop Updated Concept Paper for Annex 2

Simultaneous work streams

Principles + Annex 1 in Step-3

Annex 2 reaching Step-1

Feedback

Approximately 24 months Approximately 12-18 months

Endorsement of Concept Paper –Nov - 2019Step-4

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To be continued

https://www.ich.org/page/efficacy-guidelines

https://database.ich.org/sites/default/files/E8-R1_EWG_Step2_Presentation.pdf

https://database.ich.org/sites/default/files/E8-R1_EWG_Draft_Guideline.pdf