Questions and Answers Document - Structure and Content of Clinical Study Reports - ICH Topic E3(R1)
December 18, 2015
Our file number: 15-113539-305
Adoption of International Conference on Harmonisation of Technical Requirements for the Registration of Pharmaceuticals for Human Use (ICH) Guidance: E3 Q&A(R1): Structure and Content of Clinical Study Reports Questions & Answers (R1)
Health Canada is pleased to announce the adoption of the ICH guidance E3 Q&A(R1): Structure and Content of Clinical Study Reports Questions & Answers (R1)
This guidance has been developed by the appropriate ICH Expert Working Group and has been subject to consultation by the regulatory parties, in accordance with the ICH Process. The ICH Steering Committee has endorsed the final draft and recommended its adoption by the regulatory bodies of the European Union, Japan and USA.
In adopting this ICH guidance, Health Canada endorses the principles and practices described therein. This document should be read in conjunction with this accompanying notice and with the relevant sections of other applicable Health Canada guidances.
It is recognized that the scope and subject matter of current Health Canada guidances may not be entirely consistent with those of the ICH guidances that are being introduced as part of our commitment to international harmonization and the ICH Process. In such circumstances, Health Canada adopted ICH guidances take precedence.
Health Canada is committed to eliminating such discrepancies through the implementation of a phased-in work plan that will examine the impact associated with the adoption of ICH guidances. This will result in the amendment or, depending on the extent of revisions required, withdrawal of some Health Canada guidances.
This and other Guidance documents are available on the Health Canada website (http://www.hc-sc.gc.ca/).
Should you have any questions or comments regarding the content of the guidance, please contact:
Bureau of Metabolism, Oncology and Reproductive Sciences (BMORS)
In order to facilitate the implementation of the E3 Guideline, the International Conference on Harmonisation (ICH) Experts have developed a series of Questions and Answers.
|E3 Q&As||Approval by the ICH Steering Committee under Step 4||7 June 2012|
|E3 Q&As (R1)||Correction of minor typographical errors in the Answer to Question 6: "Section 14.3.2" was replaced by "Section 14.3.1" in the second and third paragraphs.||6 July 2012|
ICH E3: Structure and Content of Clinical Study Reports
(http://www.ich.org/products/guidelines/efficacy/article/efficacy-guidelines.html), November 1995
Table of Contents
1. Content and Structure
|Date of Approval||Questions||Answers|
Some in the pharmaceutical industry have expressed concern that the ICH E3 Guidance, Structure and Content of Clinical Study Reports (hereafter, E3), is intended as a requirement, i.e., a template that must be followed.
The fact that the ICH M4 Guidelines for the Common Technical Document (CTD) refer to specific structural elements described in E3 [for example (e.g.), Clinical Study Report [CSR] section headings] may have contributed to this interpretation.
Interpretation of E3 as a rigid template can result in presentation of redundant and suboptimal information in Clinical Study Reports (CSRs). This is a particular problem when E3 is used for studies for which it was not designed (e.g., pharmacokinetic studies or studies with health economic or quality of life outcomes).
Can ICH reaffirm that E3 is a Guideline and not a required template and that E3 may be adapted to report studies that fall outside the original scope of E3?
Yes. ICH E3 is a Guideline, not a set of rigid requirements or a template, and flexibility is inherent in its use. "The Guideline is intended to assist sponsors in the development of a report that is complete, free from ambiguity, well organized, and easy to review." Modifications and adaptations to the structure presented in the Guideline that lead to better display and communication of information are encouraged.
The introduction to E3 (page 2) clearly indicates that E3 is to be interpreted as a Guideline, not a set of requirements: "Each report should consider all of the topics described (unless clearly not relevant) although the specific sequence and grouping of topics may be changed if alternatives are more logical for a particular study. Some data in the appendices are specific requirements of individual regulatory authorities and should be submitted as appropriate. The numbering should then be adapted accordingly."
To illustrate this flexibility, consider demographic baseline information. E3 suggests presentation of this information in the efficacy evaluation, but many variations of this presentation are possible. For example, if the efficacy and safety populations differ substantially, it would be appropriate to present demographic and baseline characteristics for the safety and efficacy populations in the safety and efficacy sections or in a new section preceding the efficacy and safety results sections.
If particular types of information or topics are not addressed in E3 or if their location is not specified, this information or topic should be placed in the section that is most relevant. For example, pharmacokinetic or quality of life results could be placed in appropriately identified subsections of the efficacy and safety results sections, or they could be placed in new, appropriately identified results sections.
If a report does not address all the aspects of E3 that are relevant for a given study, this should be clearly indicated and the rationale for doing so should be provided, for example, if there is no presentation of efficacy for an efficacy study. A rationale is not necessary if sections presented in E3 are re-ordered, renamed, or deleted (if warranted by the study design) or if new sections are added.
It should be noted that E3 was developed for submission of adequate and well-controlled clinical effectiveness studies. Nevertheless, the basic principles described can be applied to other kinds of trials, such as clinical pharmacology studies and open-label safety studies, recognizing that not all sections or data presentations may be appropriate or needed for these other types of trials. Sponsors are encouraged to adapt the recommendations in the Guideline as needed (e.g., by deleting sections that are not relevant or adding needed sections that are not mentioned in the Guideline).
|2||June 2012||Can ICH reaffirm that E3 is a Guideline and not a required template and that E3 may be adapted to report studies that fall outside the original scope of E3?||The guidance given in the ICH E3 Guideline, which was developed before M4E, should be combined with the suggestions made in the M4E Guideline. Since the synopsis will be used as a stand-alone document within a Common Technical Document, it should be written so that it can be understood and interpreted on its own, i.e., without the other sections of a CSR. In addition to a brief description of the study design and critical methodological information, the synopsis should provide efficacy and safety results, as well as other critical information including data on the study population, disposition of subjects, important protocol deviations, and treatment compliance. Cross-references to other sections of the CSR should be avoided. As explained in M4E, complex or large and important studies may require a synopsis longer than 3 pages. The 10-page example given in M4E is not an absolute requirement or limit but should not need to be exceeded considerably. The use of a tabular format for the synopsis is not mandatory.|
|Date of Approval||Questions||Answers|
The CSR appendices described in the ICH E3 include material now available in the Trial Master File (TMF) in accordance with ICH E6.
Do documents available in the TMF need to be included in the CSR appendices?
Documentation needed to review the CSR should be included in the CSR appendices. It is not sufficient for such documents to be included only in the TMF, which is not submitted in the marketing application.
Documents that provide critical information on a study, such as the protocol (16.1.1), statistical methods (16.1.9), list of investigators and study sites and sample case report forms, would always be needed by reviewers assessing a study and should be included in the trial report even if they are in a TMF. Certain documents may be required for the CSR by individual countries or regions, in which case they should be included. For example, according to ICH-Good Clinical Practices (GCP), an audit certificate (16.1.8) should be provided when required by applicable law or regulation. If there is any uncertainty about whether documents should be included or not, the appropriate regulatory agency may be consulted.
Supportive documents, such as investigator CVs, ethics committee approvals, informed consent forms, and batch numbers per subject are in the TMF or clinical supply database and should generally not be included in the CSR appendices.
Any documents not submitted and subsequently requested by the regulatory authority would be expected to be provided promptly.
|4||June 2012||How can I include data not mentioned in the ICH E3 text or Appendices since the Guideline pre-dates the ICH M4 Guidelines associated with the CTD and electronic Common Technical Document (eCTD)? Specifically, what are the options for submission of data for topics such as pharmacokinetics, pharmacodynamics, pharmacogenomics (genomic markers), gene therapy, stem cells, biomarkers, devices, quality of life, assay validation, data monitoring/review committees, electrocardiogram, other safety reports, images, pictures/scans, diagnostic tests for individualized therapy, and patient-reported outcomes?||
It is appropriate to create new headings in the CSR and new Appendices for these topics. The Guideline provides for and focuses on Efficacy and Safety variables known at the time. Other topics should be well referenced in the CSR body and clearly identified in the Table of Contents.
Current submission options include:
|Date of Approval||Questions||Answers|
|5||June 2012||A subject's death could potentially be captured in two separate data listings:
There is concern that including events with fatal outcomes in 184.108.40.206 may lead to double or mis-counting of deaths. Can this issue be clarified?
It is true that the structure and definitions provided in the ICH E3 Guideline could result in deaths appearing in Section 220.127.116.11 (as per E3 numbering), Other Serious Adverse Events, if an event terminated with, or was associated with, a subject's death.
However, this should not result in double- or mis-counting of deaths. Although deaths may or may not be included in the listing for Section 18.104.22.168, all deaths should be captured in the listing for Section 22.214.171.124. That is, any subject death reported under Section 126.96.36.199 as an "other serious adverse event" with a fatal outcome would also have been captured under deaths in Section 188.8.131.52.
Section 12.2.2 of the ICH E3 Guideline states that all adverse events occurring after initiation of study treatments should be displayed in summary tables.
The example table in Section 12.2.2 of E3 (Adverse Events: Number Observed and Rate, with Subject Identifications) is really a listing that will rarely be brief enough to place in the body of the study report. Moreover, in addition to severity, relatedness, and subject identifiers (shown in the example table), each adverse event is to include the original investigator's verbatim term. How is it possible to include all of this information in a summary table? Can this table be modified?
The body of the clinical study report (ICH E3 Section 12.2.2) should include a summary table of relatively common adverse events – those occurring in at least a particular percentage of subjects who received the investigational drug. This summary tabulation compares treatment and control groups and does not include subject identifying numbers or verbatim adverse event terms.
Of note, the example table provided in Section 12.2.2 of the Guideline is not meant to be presented in Section 12.2.2 of the report, but in Section 14.3.1, which is not part of the text of the clinical study report.
The ICH E3 Guideline did not attempt to display all possible presentations of adverse event information, but rather outlined the summary table intended for Section 12.2.2 and provided an illustration of the far more detailed display that would be placed in Section 14.3.1. The example provided for Section 14.3.1, however, does not try to illustrate all possibilities, but shows individuals with adverse events by body system, severity, and perceived drug-relatedness, for treatment group "X." Listings should also display investigator's verbatim terms for each event and could be used to show demographic or disease-specific information, dosage, duration of treatment, or treatment cycle (for cancer chemotherapy).
Because it can be impractical to display all of this information in a single listing, such analyses can be presented in individual listings, e.g., by dose or other subgroup of interest. When adverse event data are presented by subgroup, however, a display of overall adverse events should also be included. For example, for a drug for subjects with chronic kidney disease, adverse events could be tabulated separately for subjects receiving or not receiving dialysis, but a table that includes adverse events in all subjects should also be included.
The listings that provide more comprehensive adverse event information, specifically subject identifiers and verbatim terms for each adverse event, should be provided in the study report, in Sections 14.3.1 and 16.2.7. If each adverse event is to be characterized extensively (i.e., many items in the listing), electronic approaches may be needed.
Section 10.2 of the ICH E3 Guideline requests an accounting of important protocol deviations. However, the flowchart in Annex IVa of E3 (Subject Disposition) recommends that data be provided on the number of subjects withdrawn from the study due to "protocol violations." Neither the term "protocol deviations" nor "protocol violations" has been previously defined by ICH.
What is the distinction between a protocol deviation, important protocol deviation, and a protocol violation? Can these terms be clarified?
Additionally, does the Guideline allow sponsors' flexibility in defining what constitutes an important protocol deviation for a trial?
A protocol deviation is any change, divergence, or departure from the study design or procedures defined in the protocol.
Important protocol deviations are a subset of protocol deviations that may significantly impact the completeness, accuracy, and/or reliability of the study data or that may significantly affect a subject's rights, safety, or well-being. For example, important protocol deviations may include enrolling subjects in violation of key eligibility criteria designed to ensure a specific subject population or failing to collect data necessary to interpret primary endpoints, as this may compromise the scientific value of the trial.
Protocol violation and important protocol deviation are sometimes used interchangeably to refer to a significant departure from protocol requirements. The word "violation" may also have other meanings in a regulatory context. However, in Annex IVa, Subject Disposition of the ICH E3 Guideline, the term protocol violation was intended to mean only a change, divergence, or departure from the study requirements, whether by the subject or investigator, that resulted in a subject's withdrawal from study participation. (Whether such subjects should be included in the study analysis is a separate question.)
To avoid confusion over terminology, sponsors are encouraged to replace the phrase "protocol violation" in Annex IVa with "protocol deviation", as shown in the example flowchart below. Sponsors may also choose to use another descriptor, provided that that the information presented is generally consistent with the definition of protocol violation provided above.
The E3 Guideline provides examples of the types of deviations that are generally considered important protocol deviations and that should be described in Section 10.2 and included in the listing in Appendix 16.2.2. The definition of important protocol deviations for a particular trial is determined in part by study design, the critical procedures, study data, subject protections described in the protocol, and the planned analyses of study data. In keeping with the flexibility of the Guideline, sponsors may amend or add to the examples of important deviations provided in E3 in consideration of a trial's requirements. Substantial additions or changes should be clearly described for the reviewer.
Figure 1: Example Flowchart - Disposition of Patients
N = 1,724 Patients receiving double-blinded medication: N = 340, Regimen A: N = 281 completed study, N = 59 Withdrawn: Adverse event (2), Unsatisfactory response, efficacy (1), failure to return (6), other medical event (5), other non-medical event (5), protocol deviation (10), patient request (12).
N = 1,724 Patients receiving double-blinded medication: N = regimen B: N = completed study, N = withdrawn: Adverse event (19), Unsatisfactory response, efficacy (2), failure to return (8), other medical event (8), other non-medical event (4), protocol deviation (10), patient request (10).
N = 1,724 Patients receiving double-blinded medication: N = regimen C: N = completed study, N = withdrawn: Adverse event (26), Unsatisfactory response, efficacy (1), failure to return (7), other medical event (4), other non-medical event (6), protocol deviation (10), patient request (25).
N = 1,724 Patients receiving double-blinded medication: N = regimen D: N = completed study, N = withdrawn: Adverse event (24), Unsatisfactory response, efficacy (1), failure to return (6), other medical event (8), other non-medical event (7), protocol deviation (6), patient request (27).
N = 1,724 Patients receiving double-blinded medication: N = regimen E: N = completed study, N = withdrawn: Adverse event (42), Unsatisfactory response, efficacy (0), failure to return (6), other medical event (14), other non-medical event (1), protocol deviation (14), patient request (15).
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