ich efficacy working groups · ich e9 (r1) addendum: statistical principles for clinical trials...

ICH Efficacy Working GroupsLaurie Letvak, MDVice PresidentHead, Clinical Development PolicyNovartis Pharmaceuticals Corporation

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Current Active ICH Efficacy Working Groups

• E6(R2) – Integrated Addendum: Good Clinical Practice

• E9(R1) – Addendum: Statistical Principles for Clinical Trials

• E11(R1) – Addendum: Clinical Investigations of Medicinal Products in the Pediatric Population

• E14 Q&As (R2) – Questions & Answers: The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non‐antiarrhythmic Drugs

• E17 – New Guideline on General Principles on planning/designing Multi‐Regional Clinical Trials

• E18 – New Guideline on Genomic Sampling Methodologies for Future Use

• M4E(R2) – Revision of M4E Guideline on Enhancing the Format and Structure of Benefit‐Risk Information in ICH

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Efficacy Topics meeting at the December 2015 ICH Meeting

• E9(R1) – Addendum: Statistical Principles for Clinical Trials

• E14 Q&As (R2) – Questions & Answers: The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non‐antiarrhythmic Drugs

• E17 – New Guideline on General Principles on planning/designing Multi‐Regional Clinical Trials

• E18 – New Guideline on Genomic Sampling Methodologies for Future Use

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Open Public Consultations

• E6(R2) – Integrated Addendum: Good Clinical Practice

• M4E(R2) – Revision of M4E Guideline on Enhancing the Format and Structure of Benefit‐Risk Information in ICH

Please refer to the ICH website for more details (www.ich.org).

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E6(R2) INTEGRATED ADDENDUM: GOOD CLINICAL PRACTICE

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E6(R2) Integrated Addendum: Good Clinical PracticeGoal

– To facilitate innovative approaches to good clinical practice (GCP) to better ensure human subject protection and clinical data quality

Discussion topics within the E6(R2) Expert Working Group– Quality risk management– Quality by design processes– Emphasizing upfront assessment of risks specific to a study design and

protocol– Risk‐based monitoring, focusing on critical study elements– Use of technological tools to ensure robust conduct, oversight, and

reporting

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E6(R2) Integrated Addendum: Good Clinical Practice

Format– In this “Integrated” Addendum, changes were integrated directly into

several sections of the parental Guideline, as opposed to a consolidated addendum at the end.

Current Activities– The E6(R2) Integrated Addendum reached Step 2 of the ICH process in

June 2015.– E6(R2) is undergoing public consultation as part of Step 3 of the ICH

process now.– Current Open Public Consultations (See ICH website for details)

• ICH Website• EU • FDA• Health Canada

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E9(R1) – ADDENDUM: STATISTICAL PRINCIPLES FOR CLINICAL TRIALS

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ICH E9 (R1) Addendum: Statistical Principles for Clinical Trials

BackgroundAn Addendum was proposed to provide clarification on the E9 guideline developed in 1998 to describe an agreed framework for planning, conducting and interpreting sensitivity analyses of clinical trial data.

GoalFocus on planning clinical trials better by looking at:

– How treatment benefit will be quantified (Estimand)– How you will use your data at end of trial (Estimator)– How you will deal with problems like missing data and other aspects

(Sensitivity analyses)

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ICH E9 (R1) Addendum: Statistical Principles for Clinical Trials

Plans for December 2015 ICH Meeting• Progress towards finalization of the Step 1 Technical

Document and progress the drafting of the technical appendix.

• Feedback from regional discussions, both with statisticians and non‐statisticians.

• Continue methodological discussions, the review of existing ICH guidelines and of relevant case studies.

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E11(R1) – ADDENDUM: CLINICAL INVESTIGATIONS OF MEDICINAL PRODUCTS IN THE PEDIATRIC POPULATION

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Background• Pediatric medical product development has advanced since

the current ICH E11 guideline was adopted in 2000.

• United States (US) and the European Union (EU) now have permanent legislation that mandates plans for pediatric medical product development

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E11(R1): Clinical Investigation of Medicinal Products in the Pediatric Population

Goal

• Address gaps in the current E11 guidance due to advancement without a parallel development of harmonized guidance in the following areas:– Targeted scientific and technical issues relevant to pediatric

populations– Regulatory requirements for pediatric study plans, and – Infrastructure for undertaking complex trials in pediatric patient

populations has been considerably advanced in the last decade, without a parallel development of harmonized guidance in these areas

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Format • No editing of existing text of E11 Clinical Investigation of

Medicinal Products in the Pediatric Population, December 2000

• Addition of an Annex I with Introduction, reference to existing E11 and new/updated sub‐sections

Current Activities• The working group has been working virtually via

teleconference and email, and will not meet during the face to face December 2015 ICH meeting.

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Proposed addendum topics – Commonality of Content– Age definitions– Extrapolation of data– Ethical Considerations– Clinical Study Methodology– Pediatric Formulations– Model‐Informed Drug Discovery Development (MID3)

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E14 Q&AS (R2) – QUESTIONS & ANSWERS: THE CLINICAL EVALUATION OF QT/QTC INTERVAL PROLONGATION AND PROARRHYTHMIC POTENTIAL FOR NON‐ANTIARRHYTHMIC DRUGS

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Background• June 2015 ‐ ICH E14 Guideline finalized • 17 revisions followed through a Q&A document to provide

clarity and technical improvements– June 2008 (n=8)– April 2012 (n=5)– March 2014 (n=4)

• E14 Expert Working Group became “E14/S7B Discussion group” to monitor several ongoing development efforts

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E14 Q&As (R2) – Proarrhythmic Potential for Non‐antiarrhythmic Drugs


Goal• Revise the E14 Q&A on Concentration‐Response Modeling to

generate harmonized guidance on how concentration response modeling could be used for regulatory decision making.

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Plans for December 2015 ICH Meeting• Finalize the revised Q&A on use of concentration‐response

relationships for regulatory decision making. • Preliminary recommendation to ICH SC regarding whether to

re‐open ICH E14 for complete revision.

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E17 – NEW GUIDELINE ON GENERAL PRINCIPLES ON PLANNING/DESIGNING MULTI‐REGIONAL CLINICAL TRIALS

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E17 – New Guideline on General Principles on planning/designing Multi‐Regional Clinical Trials

Background• Drug development has become increasingly global.• While MRCTs for regulatory submission has widely been conducted

in ICH regions and beyond, regulatory agencies are currently facing challenges in evaluating data from MRCTs for drug approval.

Goal• Development of a harmonized ICH guideline to promote

appropriate conduct of MRCTs, focusing on scientific issues in planning/designing MRCTs.

• This new Guideline will complement the guidance on MRCTs provided in ICH E5(R1) Guideline and facilitate MRCT data acceptance by multiple regulatory agencies.

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Objectives• Provide general principles for planning and designing MRCTs • Promote use of MRCTs in regulatory submissions spanning

multiple regions • Minimize conflicting submission requirements from regulatory

agencies

The E17 Expert Working Group will meet face to face at the December 2015 meeting to make progress toward completing the Step 1 document.

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Table of Contents• Introduction

– Objectives, background, scope, and general principles• General recommendations

– Strategy‐related points (value of MRCTs, basic requirements, regulatory interactions)

– Clinical trial design and protocol‐related topics• Pre‐consideration of regional variability on efficacy/safety• Subject selection• Dose selection• Choice of endpoints• Estimation of sample size and allocation to regions• Collecting and handling efficacy/safety data• Statistical analysis planning• Selection of comparator• Handling concomitant medications

– Glossary

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E18 – NEW GUIDELINE ON GENOMIC SAMPLING METHODOLOGIES FOR FUTURE USE

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Background– Genomic information is increasingly included in drug labels, but sample

collection rates remain low– Storage of genomic samples and data in clinical studies may be subject to

national laws and regulations

Goal– Address regional difference across FDA, EMA, PMDA on DNA sampling– Clarify technical aspects relating to collection, handling and storage of

genomic samples for future use

The E18 Expert Working Group will meet face to face at the December 2015 meeting to make progress toward completing the Step 1document.

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E18 – New Guideline on Genomic Sampling Methodologies for Future Use

1. INTRODUCTION• 1.1 Objective(s) of the Guideline• 1.2 Background• 1.3 Scope of the Guideline• 1.4 General Principles2. GUIDELINES• 2.1 Rationale for genomic sampling• 2.2 Genomic sampling

2.2.1 Collection and Processing of sample

2.2.2 Transport, Storage and Disposition of sample

• 2.3 Genomic data2.3.1 Type of genomic data2.3.2 Generation of genomic data2.3.3 Handling and storage of genomic data

• 2.4 Privacy and confidentiality2.4.1 Coding2.4.2 Access to the genomic data

• 2.5 Emerging topics

Draft Table of Contents

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E18 – New Guideline on Genomic Sampling Methodologies for Future Use

M4E(R2) – REVISION OF M4E GUIDELINE ON ENHANCING THE FORMAT AND STRUCTURE OF BENEFIT‐RISK INFORMATION IN ICH (CTD SECTION 2.5.6)

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Background– Current ICH guideline is limited in detail and lacks a recommended structure

for the benefit‐risk (B‐R) assessment– Regulators observe significant variability in how applicants describe their

benefit‐risk assessment in regulatory submissions

Goal– Revise Section 2.5.6 “Benefits and Risks Conclusions” of ICH M4E guideline to

standardize the format and content of benefit‐risk information– Standardization should increase efficiency in communication of the benefit‐

risk assessment between industry and regulators– Out of scope: specifying a recommended methodology in conducting benefit‐

risk assessments

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M4E(R2) – Revision of M4E Guideline on Enhancing the Format and Structure of Benefit‐Risk Information in ICH

M4E(R2) – Revision of M4E Guideline on Enhancing the Format and Structure of Benefit‐Risk Information in ICH

Current Activities– M4E(R2) reached Step 2 of the ICH process in August 2015.– Undergoing public consultation as part of Step 3 of the ICH process

now.– Current Open Public Consultations (See ICH website for details)

• ICH Website• EU • FDA• MHLW• Health Canada

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Source

www.ICH.org

• Concept Papers• Business Plans• Work Plans

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ich efficacy working groups · ich e9 (r1) addendum: statistical principles for clinical trials...

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