Efficacy Guidelines

The work carried out by ICH under the Efficacy heading is concerned with the design, conduct, safety and reporting of clinical trials. It also covers novel types of medicines derived from biotechnological processes and the use of pharmacogenetics/ pharmacogenomics techniques to produce better targeted medicines.

The ICH harmonised Guideline was finalised under Step 4 in October 1994. This document gives recommendations on the numbers of patients and duration of exposure for the safety evaluation of drugs intended for the long-term treatment of non-life-threatening conditions.

  • E1 Guideline Pdf
  • The ICH Harmonised Guideline was finalised under Step 4 in October 1994. This document gives standard definitions and terminology for key aspects of clinical safety reporting. It also gives guidance on mechanisms for handling expedited (rapid) reporting of adverse drug reactions in the investigational phase of drug development.

  • E2A Guideline Pdf
  • In July 2013, the ICH Steering Committee endorsed the establishment of the IWG on E2B(R3) to assist with the implementation of the E2B(R3) Implementation Guide (published in July 2013) and help facilitate transition from E2B(R2) to E2B(R3). Included in its tasks is support for the use of constrained ISO IDMP terminologies in ICSRs, as well as maintenance of technical documents related to E2B(R3). In November 2014, the IWG finalised the first version of Questions & Answers (Q&As) to clarify questions and comments for E2B(R3) implementation. The E2B(R3) Implementation Package, Q&As and further information is available on the ESTRI page.

    In July 2013, the ICH Steering Committee endorsed the establishment of the IWG on E2B(R3) to assist with the implementation of the E2B(R3) Implementation Guide (published in July 2013) and help facilitate transition from E2B(R2) to E2B(R3). Included in its tasks is support for the use of constrained ISO IDMP terminologies in ICSRs, as well as maintenance of technical documents related to E2B(R3). In November 2014, the IWG finalised the first version of Questions & Answers (Q&As) to clarify questions and comments for E2B(R3) implementation. The E2B(R3) Implementation Package, Q&As and further information is available on the ESTRI page.

    Questions and Answers

  • E2B-R3_QA document Pdf

  • Endorsed Document

  • E2B_R3 Q&As Concept Paper Pdf
  • E2B_R3 Q&As WorkPlan Pdf
  • In July 2013, the ICH Steering Committee endorsed the establishment of the IWG on E2B(R3) to progress implementation activities and ensure transition from E2B(R2) to E2B(R3). The E2B(R3) Implementation Package, Q&As and further information is available on the ESTRI page.

    Endorsed Document

  • E2B-R3 EWGIWG WorkPlan Pdf
  • The ICH Harmonised Guideline was finalised under Step 4 in November 1996. This document gives guidance on the format and content of safety updates, which need to be provided at intervals to regulatory authorities after products have been marketed. The Guideline is intended to ensure that the worldwide safety experience is provided to authorities at defined times after marketing with maximum efficiency and avoiding duplication of effort.

    Based on the comments made by the members of the Expert Working Group on CIOMS V recommendations and the PhRMA-EFPIA working document, an addendum has been finalised and reached Step 4 in February 2003 (R1).

    The revised (R2) Guideline reached Step 4 of the ICH process in November 2012. The purpose of this Guideline’s revision is to ensure that the periodic safety update reports for marketed drugs have the role of being periodic benefit-risk evaluation reports by covering: safety evaluation, evaluation of all relevant available information accessible to marketing authorisation holders (MAHs) and benefit-risk evaluation.

    Guideline

  • E2C_R2 GuidelinePdf

  • Endorsed Documents

  • E2C_R2 Concept Paper Pdf
  • E2C_R2 Business Plan Pdf
  • The revision E2C(R2) to E2C has introduced new concepts and principles linked to an evolution of the traditional PSUR from an interval safety report to cumulative benefit-risk report and with a change in focus from individual case reports to more aggregate data evaluation. This supplementary Questions and Answers document finalised under Step 4 in March 2014 intends to facilitate practical implementation of the PBRER, including points to consider in addressing some of the more novel aspects of the new periodic safety report.

    Question And Answers

  • E2C R2 Q&As Pdf

  • Endorsed Documents

  • E2CR2_Q&As Concept Paper Pdf
  • E2CR2_Q&As WorkPlan Pdf
  • The ICH Harmonised Guideline was finalised under Step 4 in November 2003. This document provides a standardised procedure for post-approval safety data management and the guidance for gathering and reporting information. This Guideline is based on the content of ICH E2A Guideline, with consideration as to how the terms and definitions can be applied in the post-approval phase of the product life cycle.

    Guideline

  • E2D Guideline Pdf

  • Endorsed Documents

  • E2D Concept Paper Pdf
  • This topic was endorsed by the ICH Assembly in June 2019. The E2D(R1) EWG is working on the revision of the of the E2D Guideline “Post-Approval Safety Data Management: Definitions and Standards for Expedited Reporting” with a view to clarifying the management of post-approval safety information from new or increasingly used data sources including the need to adapt definitions and standards.

    Endorsed Documents

  • E2D-R1 Concept Paper Final Pdf
  • E2D-R1 Final Business Plan Pdf
  • E2D-R1 EWG WorkPlan Pdf
  • The ICH Harmonised Guideline was finalised under Step 4 in November 2004. This Guideline is intended to aid in planning pharmacovigilance activities, especially in preparation for the early post-marketing period of a new drug (in this Guideline, the term "drug" denotes chemical entities, biotechnology-derived products, and vaccines). The main focus of this Guideline is on a Safety Specification and Pharmacovigilance Plan that might be submitted at the time of licence application.

    Guideline

  • E2E Guideline Pdf

  • Endorsed Document

  • E2E_Concept Paper Pdf
  • The ICH Harmonised Guideline was finalised under Step 4 in August 2010. The Development Safety Update Report (DSUR) proposed in this Guideline is intended to be a common standard for periodic reporting on drugs under development (including marketed drugs that are under further study) among the ICH regions. The main focus of the DSUR is data and findings from interventional clinical trials (referred to as "clinical trials") of drugs and biologicals that are under investigation, whether or not they have a marketing approval.

    Following the completion of the E2F Step 4 Guideline, the E2F EWG developed DSUR Examples for commercial and non-commercial sponsors to help with the use of the E2F Guideline. It should be noted that these documents are only examples and therefore did not go through the Formal ICH Procedure.

    Guideline

  • E2F Guideline Pdf

  • Endorsed Documents

  • E2F_Concept Paper Pdf
  • E2F_Business Plan Pdf

  • WG Presentation / Trainings

  • E2F_Presentation DSUR Pdf

  • Deliverables

  • E2F_Example Non Commercial DSUR Pdf
  • E2F_Example Commercial DSUR Pdf
  • The ICH Harmonised Guideline was finalised under Step 4 in November 1995. This document describes the format and content of a clinical study report that will be acceptable to all regulatory authorities of the ICH regions. It consists of a core report suitable for all submissions and appendices that need to be available but will not be submitted in all cases.

  • E3 Guideline Pdf
  • Since reaching Step 4 and publication within the ICH regions, experiences by all parties with the implementation of the E3 Guideline have resulted in the need for some clarification. This supplementary Questions and Answers document intends to clarify key issues. In July 2012, minor typographical errors were corrected in the Answer to Question 6 and the document was renamed R1.

    Question And Answers

  • E3 Q&As R1 Q&As Pdf

  • endorsed Document

  • E3_Q&As R1 Concept Paper Pdf
  • The ICH Harmonised Guideline was finalised under Step 4 in March 1994. This document gives recommendations on the design and conduct of studies to assess the relationships among dose, drug-concentration in blood, and clinical response throughout the clinical development of a new drug.

    Guideline

  • E4 Guideline Pdf
  • The ICH Harmonised Guideline was finalised under Step 4 in February 1998. This document addresses the intrinsic characteristics of the drug recipient and extrinsic characteristics associated with environment and culture that could affect the results of clinical studies carried out in regions, and describes the concept of the "bridging study" that a new region may request to determine whether data from another region are applicable to its population.

  • E5_R1 Guideline Pdf
  • Since reaching Step 4 and publication within the ICH regions, experiences by all parties with the implementation of the E5 Guideline have resulted in the need for some clarification. This supplementary Questions and Answers document intends to clarify key issues.

    Questions And Answers

  • E5_Q&As R1 Q&As Pdf
  • The first version of the ICH E6 Good Clinical Practice (GCP) Guideline was finalised in 1996 describing the responsibilities and expectations of all participants in the conduct of clinical trials, including investigators, monitors, sponsors and IRBs. GCP covers aspects of monitoring, reporting and archiving of clinical trials, and incorporates addenda on the Essential Documents and on the Investigator's Brochure.

    This Harmonised Guideline has been amended in 2016 with an integrated Addendum to encourage implementation of improved and more efficient approaches to clinical trial design, conduct, oversight, recording and reporting, while continuing to ensure human subject protection and reliability of trial results. Standards regarding electronic records and essential documents intended to increase clinical trial quality and efficiency have also been updated.

    Endorsed Document

  • E6_R2 Concept Paper Pdf
  • E6_R2 Business Plan Pdf

  • Other Document

  • E6_R2 Addendum Pdf

  • We Presentations/ Trainings

  • E6_R2_Step_4 Presentation Pdf
  • This topic was endorsed by the ICH Assembly in June 2019.

    The E6(R3) EWG is working on the revision of the E6(R2) Guideline “Good Clinical Practice” (GCP) with a view to addressing the application of GCP principles to the increasingly diverse trial types and data sources being employed to support regulatory and healthcare related decision-making on drugs, and provide flexibility whenever appropriate to facilitate the use of technological innovations in clinical trials. Additional information may also be found in ICH Reflection Paper on “GCP Renovation”.

    Endorsed Documents

  • E6-R3 Final Concept Paper Pdf
  • E6-R3 Final Business Plan Pdf
  • E6-R3 EWG WorkPlan Pdf
  • The ICH Harmonised Guideline was finalised under Step 4 in June 1993. This document provides recommendations on the special considerations, which apply in the design and conduct of clinical trials of medicines that are likely to have significant use in the elderly.

    Guideline

  • E7 Guideline Pdf
  • Since reaching Step 4 and publication within the ICH regions, experiences by all parties with the implementation of the E7 Guideline have resulted in the need for some clarification. This supplementary Questions and Answers document intends to clarify key issues.

    Question And Answers

  • E7 Q&As Pdf

  • Endorsed Document

  • E7_Q&As Concept Paper Pdf
  • The ICH Harmonised Guideline was finalised under Step 4 in July 1997. This document sets out the general scientific principles for the conduct, performance and control of clinical trials. The Guideline addresses a wide range of subjects in the design and execution of clinical trials.

    Guideline

  • E8 Guideline Pdf
  • ICH is proposing a modernisation of ICH E8 in order to incorporate the most current concepts achieving fit-for-purpose data quality as one of the essential considerations for all clinical trials. The revision would propose to: (1)identify a basic set of critical-to-quality factors that can be adapted to different types of trials to support the meaningfulness and reliability of trial results and to protect human subjects; (2)address a broader range of trial designs and data sources; (3)provide an updated cross-referencing of all other relevant ICH Guidelines that should be referred to when planning clinical studies. The modernisation of ICH E8 is the first step towards the GCP Renovation initiated in 2017.

    On Thursday, 31 October 2019, as part of the GCP renovation plan, ICH held a public meeting entitled “ICH Global Meeting on E8(R1) Guideline on General Considerations for Clinical Trials” hosted by FDA, United States at their headquarters in Silver Spring, MD, USA. The purpose of the public meeting was to provide information and solicit input from a broad range of non-ICH Member/Observer stakeholders on the draft revised E8(R1) Guideline “General Considerations for Clinical Trials.” Further information, including the summary report of the meeting, is available on the GCP renovation page.

    Guideline

  • E8-R1_EWG_Draft_Guideline Pdf

  • WG Presentations / Trainings

  • E8-R1_EWG Step2 Presentation Pdf

  • Endorsed Document

  • E8-R1_EWG Concept Paper Pdf
  • E8-R1_EWG Business Plan Pdf
  • E8-R1_EWG WorkPlan Pdf
  • The ICH Harmonised Guideline was finalised under Step 4 in February 1998. This document sets out the principles of statistical methodology applied to clinical trials for marketing applications submitted in the ICH regions. The principles outlined in this guidance are primarily relevant to clinical trials conducted in the later phases of development, many of which are confirmatory trials of efficacy.

    Guideline

  • E9 Guideline Pdf

  • Endorsed Document

  • Q9_Concept Paper Pdf
  • Q9 Business Plan Pdf
  • This topic was endorsed by the ICH Steering Committee in October 2014. An Addendum was proposed to provide clarification on E9 and an update on the choice of estimand in clinical trials to describe an agreed framework for planning, conducting and interpreting sensitivity analyses of clinical trial data. This Addendum is proposed to focus on statistical principles related to estimands and sensitivity analysis, not on the use or acceptability of specific statistical procedures or methods. While a variety of mid-stage and late-stage clinical trials may be in scope, the primary focus of the Addendum will be on confirmatory clinical trials.

    Guidelines

  • E9-R1 Step4 Guideline Pdf

  • WG Trainings/ Presentations

  • E9-R1_EWG Step2 Training Material Pdf

  • Endorsed Documents

  • E9-R1 EWG Concept Paper Pdf
  • E9-R1 EWG WorkPlan Pdf
  • The ICH harmonised Guideline was finalised under Step 4 in July 2000. This document addresses the choice of control groups in clinical trials considering the ethical and inferential properties and limitations of different kinds of control groups. It points out the assay sensitivity problem in active control equivalence / non-inferiority trials that limits the usefulness of trial design in many circumstances.

    Guideline

  • E10 Guideline Pdf
  • Since the adoption of the ICH E11 Guideline on Clinical Investigation of Medicinal Products in the Pediatric Population in 2000, pediatric drug development has been enhanced by advancements in several areas of general adult drug development. Targeted scientific and technical issues relevant to pediatric populations, regulatory requirements for pediatric study plans, and infrastructures for undertaking complex trials in pediatric patient populations has been considerably advanced in the last decade, without a parallel development of harmonised guidance in these areas. This Addendum is proposed to address new scientific and technical knowledge advances in pediatric drug development.

    Other Documents

  • E11_R1 Addendum Pdf

  • Endorsed Document

  • E11_R1 Concept Paper Pdf

  • WG Presenations / trainings

  • E11_R1 Step4 Presentation Pdf
  • This topic was endorsed by the ICH Assembly in June 2017. This new ICH Guideline is proposed for harmonisation of methodologies and strategies to incorporate paediatric extrapolation into overall drug development plans and therefore improve the speed of access to new drugs for paediatric patients while limiting the number of children required for enrolment in clinical trials.

    The future E11A Guideline would address and align terminology related to paediatric extrapolation; provide information on various approaches that can be utilised to support the use of paediatric extrapolation; discuss a systematic approach to use of paediatric extrapolation; and provide information on study designs and statistical analysis methods used when incorporating paediatric extrapolation into a paediatric drug development plan.

    Endorsed Document

  • E11A_EWG Concept Paper Pdf
  • E11A_EWG Business Plan Pdf
  • E11A_EWG WorkPlan Pdf
  • This therapeutic area document considers the Clinical Evaluation of New Antihypertensive Drugs. It provides a set of "Principles" on which there is general agreement among all ICH regions covering endpoints and trial designs. Since there are a few differences in the requirements of the regions that have not been harmonised, this document should be considered an "ICH Principle Document" rather than an "ICH Guideline". It will not be subject to the usual procedures leading to a fully harmonised document.

    Other Document

  • E12 Guideline Pdf
  • The ICH harmonised Guideline was finalised under Step 4 in May 2005. This document provides recommendations to sponsors concerning the design, conduct, analysis, and interpretation of clinical studies to assess the potential of a drug to delay cardiac repolarisation. This assessment should include testing the effects of new agents on the QT/QTc interval as well as the collection of cardiovascular adverse events.

    The investigational approach used for a particular drug should be individualised, depending on the pharmacodynamic, pharmacokinetic, and safety characteristics of the product, as well as on its proposed clinical use. The assessment of the effects of drugs on cardiac repolarisation is the subject of active investigation. When additional data (non-clinical and clinical) are accumulated in the future, this document may be reevaluated and revised.

    Guideline

  • E14 Guideline Pdf
  • Since reaching Step 4 and publication within the ICH regions, experiences by all parties with the implementation of the E14 Guideline have resulted in the need for some clarification. The Questions and Answers developed by the E14 Implementation Working Group (IWG) are intended to facilitate the implementation of the E14 Guideline by clarifying key issues. The document with the first set of Q&As was finalised under Step 4 in June 2008. In April 2012, a second set of Q&As was developed and approved by the Steering Committee for integration in the Q&A document (E14 Q&As (R1)).

    In March 2014, a third set of Q&As was developed and approved by the Steering Committee for integration in the Q&A document (E14 Q&As (R2)). In December 2015, the Question #5.1 of the E14 Q&As (R2) was revised to generate harmonised guidance on how concentration response modelling could be used for regulatory decision making. The document was approved by the Assembly for integration in the Q&A document (E14 Q&As (R3)).

    Question And answers

  • E14 Q&As R3 Q&As Pdf

  • Endorsed Document

  • E14 Q&As R3 Concept Paper Pdf

  • WG Presentations And Trainings

  • E14_Q&As_R3_Step4_Presentation Pdf
  • In November 2018, the Assembly endorsed the establishment of the E14/S7B Implementation Working Group (IWG) for the development of Q&As for the ICH E14 and ICH S7B Guidelines. ICH S7B and ICH E14 describe non-clinical and clinical risk assessment strategies to inform the potential risk for proarrhythmia of a test substance and contribute to the design of clinical investigations. Emergent data over the past several years demonstrate that different experimental results can arise for the same compound as a function of the study conditions used in non-clinical assays. The E14/S7B IWG will build on work done by the former E14/S7B Discussion Group (DG) which discussed the advances in science and methods related to the clinical assessment of QT prolongation and worked on the Comprehensive in vitro Proarrhythmia Assessment (CiPA) initiative.

    The E14/S7B IWG will provide guidance regarding best practices for the design, conduct, analysis, interpretation and reporting of in vitro, in silico and in vivo non-clinical assays in order for these assays to influence non-clinical and clinical evaluations. The Q&As will be developed in two stages to allow for more rapid impact of novel approaches on S7B and subsequently E14 for evolving drug candidates, enabling a more efficient, comprehensive and mechanism-driven process. The objective of the first stage of the proposed harmonisation work is to provide clarity on how to standardise assays such as multi-ion channel assays, in silico models, in vitro human primary and induced pluripotent cardiomyocyte assays and in vivo evaluation, and apply these learnings to guide predictions and subsequent clinical assessment. These efforts will provide a customisable non-clinical strategy that is more informative for clinical development.

    Endorsed Documents

  • E14S7B_IWG Concept Paper Pdf
  • E14-S7B IWG WorkPlan Pdf
  • The ICH Harmonised Guideline was finalised under Step 4 in November 2007. This Guideline contains definitions of key terms in the discipline of pharmacogenomics and pharmacogenetics, namely genomic biomarkers, pharmacogenomics, pharmacogenetics and genomic data and sample coding categories. The validation and qualification processes for genomic biomarkers, evidence for their intended use and acceptance criteria across ICH regions are outside of the scope of this guideline. As new scientific knowledge in the discipline of pharmacogenomics and pharmacogenetics emerges, the current guidance will be reviewed and expanded if appropriate.

    Guideline

  • E15 Guideline Pdf

  • Endorsed Document

  • E15_Concept Paper Pdf
  • E15_Business Plan Pdf
  • The ICH Harmonised Guideline was finalised under Step 4 in August 2010. The Guideline describes recommendations regarding context, structure, and format of regulatory submissions for qualification of genomic biomarkers, as defined in ICH E15.

    Guideline

  • E16 Guideline Pdf

  • Endorsed Documents

  • E16_Concept Paper Pdf
  • E16_Business Plan Pdf

  • WG Presentations / Trainings

  • ICH E16 Step 4 presentation Pdf
  • The ICH Harmonised Guideline was finalised under Step 4 in November 2017. This Guideline provides guidance on general principles on planning/designing Multi-Regional Clinical Trial (MRCT). Drug development has been globalised and MRCT for regulatory submission has widely been conducted in ICH regions and beyond. Regulatory agencies are currently facing some challenges in evaluating data from MRCTs for drug approval and it was deemed necessary to developed a Harmonised international Guideline to promote conducting MRCT appropriately, especially focusing on scientific issues in planning/designing MRCTs. This Guideline complements the guidance on MRCTs provided in ICH E5(R1) Guideline and facilitates MRCT data acceptance by multiple regulatory agencies.

    An extensive set of training materials including 7 modules has been developed to promote the efficient and consistent implementation of the E17 Guideline in the context of an evolving drug development environment.

    Guideline

  • E17EWG_Step4 Pdf

  • Endorsed Documents

  • E17EWG Final Concept Paper Pdf
  • E17EWG Final Business Plan Pdf

  • WG Presentations / Trainings

  • E17EWG_Step 4 Presentation Pdf
  • The ICH Harmonised Guideline was finalised under Step 4 in August 2017. This document provides Harmonised principles of genomic sampling and management of genomic data in clinical studies. This Guideline will facilitate the implementation of genomic studies by enabling a common understanding of critical parameters for the unbiased collection, storage, and optimal use of genomic samples and data.

    It is intended to foster interactions amongst stakeholders, including drug developers, investigators and regulators, and to encourage genomic research within clinical studies.

    Guideline

  • E18 Guideline Pdf

  • Endorsed Documents

  • E18_Concept Paper Pdf
  • E18_Business Plan Pdf

  • WG Presentations

  • E18_Step4 Presentation Pdf
  • This topic was endorsed by the ICH Assembly in November 2016. This new Guideline is proposed to provide Harmonised guidance on when it would be appropriate to use a targeted approach to safety data collection in some late-stage pre-marketing or post-marketing studies, and how such an approach would be implemented. Recognising that protection of patient welfare during drug development is critically important, unnecessary data collection may be burdensome to patients, and serve as a disincentive to participation in clinical research.

    By tailoring safety data collection in some circumstances, the burden to patients would be reduced, a larger number of informative clinical studies could be carried out with greater efficiency, studies could be conducted with greater global participation, and the public health would be better served. The proposed Guideline would be consistent with risk-based approaches and quality-by-design principles.

    Guideline

  • E13 Guideline Pdf

  • Endorsed Documents

  • E19_EWG Draft Guideline Pdf
  • E19_EWG Business_Plan Pdf
  • E19_EWG WorkPlan
  • The ICH harmonised Guideline was finalised under Step 4 in May 2005. This document provides recommendations to sponsors concerning the design, conduct, analysis, and interpretation of clinical studies to assess the potential of a drug to delay cardiac repolarisation. This assessment should include testing the effects of new agents on the QT/QTc interval as well as the collection of cardiovascular adverse events.

    The investigational approach used for a particular drug should be individualised, depending on the pharmacodynamic, pharmacokinetic, and safety characteristics of the product, as well as on its proposed clinical use. The assessment of the effects of drugs on cardiac repolarisation is the subject of active investigation. When additional data (non-clinical and clinical) are accumulated in the future, this document may be reevaluated and revised.

    Endorsed Documents

  • E20_Final Concept Paper Pdf
  • E20_Final Business Plan Pdf
  • E20_EWG WorkPlan Pdf