“A clinical study report (CSR) on a clinical trial is a document, typically very long, providing much detail about the methods and results of a trial.
A CSR is a scientific document addressing efficacy and safety, not a sales or marketing tool; its content is similar to that of a peer-reviewed academic paper.
The clinical and statistical description, presentations, and analyses are integrated into single report, incorporating tables and figures into main text of the report or at the end of the text, with appendices containing such information as the protocol, sample case report forms, investigator-related information, information related to the test drugs/investigational products including active control/comparators, technical statistical documentation, related publications, patient data listings, and the technical statistical details such as derivations, computations, analyses, and computer output.
While this guideline is specifically intended for effectiveness and safety research, the basic concepts and framework outlined can be applicable to other types of research, such as clinical pharmacology.
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The report will provide a straightforward description of how the study’s vital design features were chosen and adequate detail about the study’s strategy, procedures, and behavior so there is no confusion about how the research was performed.
The report and its appendices should also include ample individual patient data, including demographic and longitudinal data, and analytical method information, to allow the vital analyzes to be repeated if the authorities wish to.
It is also particularly important that all analyses, tables, and figures carry, in text or as part of the table, clear identification of the set of patients from which they were generated.
The individual study’s full integrated report will provide the most thorough review of specific adverse effects or laboratory anomalies, but these should generally be re-examined as part of an overall safety examination of all available evidence for any use.
The report will explain demographic and other potentially predictive characteristics of the study population and present data for demographic (e.g., age, sex , race, weight) and other (e.g., renal or hepatic function) subgroups where the research is broad enough to permit this, in order to identify possible variations in effectiveness or health.
The provisions of this guideline should be used in conjunction with other ICH guidelines.
1. TITLE PAGE
The title page should contain the following information:
- Study title.
- Name of test drug/investigational product.
- Indication studied.
- If not apparent from the title, a brief (one to two sentences) description giving design (parallel, cross-over, blinding, randomized) comparison (placebo, active, dose/response), duration, dose, and patient population.
- Name of the sponsor.
- Protocol identification (code or number).
- The development phase of the study.
- Study initiation date (the first patient enrolled or any other verifiable definition).
- Date of early study termination, if any. Study completion date (the last patient completed).
- Name and affiliation of principal or coordinating investigator(s) or sponsor’s responsible medical officer.
- Name of company/sponsor signatory (the person responsible for the study report within the company/sponsor).
- The name, telephone number, and fax no. of the company/sponsor contact persons for questions arising during the review of the study report should be indicated on this page or in the letter of application.
- A statement indicating whether the study was performed in the compliance with good clinical practice (GCP), including the archiving of essential documents.
- Report Date (identify any earlier reports from the same study by title and date)
2. SYNOPSIS:
A brief synopsis (usually limited to three pages) that summarizes the study should be provided (see Annex I of the guideline for an example of the synopsis format used in Europe).
The synopsis should include numerical data in order to illustrate results, not just text or p-values.
3. TABLE OF CONTENTS FOR THE INDIVIDUAL CLINICAL STUDY REPORT
The table of contents should include:
- The page number or other section locating content, including summary tables, statistics, and graphs.
- A list and the locations given for the appendices, tabulations, and forms for any case study.
4. LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
A list should be included of the abbreviations and lists and meanings of specific or unusual words or units of measurement used in the study. Abbreviated words should be written out and the abbreviation indicated in parentheses should appear in the text at first appearance.
5. ETHICS
- 5.1 Independent Ethics Committee (IEC) or Institutional Review Board (IRB)
It should be confirmed that an IEC or IRB has been reviewing the study and any amendments. A list of all consulted IECs or IRBs should be given in Appendix 16.1.3 and the name of the committee chair should be provided if requested by the regulatory authority
- 5.2 Ethical Conduct of the Study
It should be confirmed that the study was conducted in accordance with ethical principles that have their origins in the Declaration of Helsinki.
- 5.3 Patient Information and Consent
How and when informed consent in relation to patient enrollment (e.g. at allocation, prescreening) has been obtained should be described.
Appendix 16.1.3 will include descriptive written information for the patient (if any) and a description of the patient consent form used.
6. INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE
The study’s administrative structure (e.g., principal investigator, organizing investigator, steering committee, administration, control and assessment committees, agencies, statisticians, central laboratory facilities, contract research organization (C.R.O.), clinical trial supply management) should be briefly defined in the report’s collection.
A list of the investigators with their affiliations, their role in the study and their qualifications (curiculum vitae or equivalent) should be provided in Appendix 16.1.4.
A similar list should also be set out in Appendix 16.1.4 for other individuals whose presence adversely influenced the conduct of the research.
The listing should include:
A. Investigators.
B. Any other person carrying out observations of primary or other major efficacy variables
C. The author s of the report, including the responsible biostatistician(s).
Where regulatory authorities include the signatures of the principal or coordinating inspectors, these should be included in Appendix 16.1.5 (see a sample form in Annex II). Where these are not needed, a signature should be given in Appendix 16.1.5 for the responsible medical officer of the sponsor.
7. INTRODUCTION
The introduction will include a brief statement (maximum: one page) placing the study in the context of the development of the test drug / research product, relating to that development the essential features of the study ( e.g. rationale and goals, target population, treatment, length, primary endpoints).
It is necessary to identify or describe any guidelines that have been followed in the development of the protocol or any other agreements / meetings between the sponsor / company and regulatory authorities relevant for the particular study.
8. STUDY OBJECTIVES:
A statement describing the overall purpose(s) of the study should be provided.
9. INVESTIGATIONAL PLAN
- 9.1 Overall Study Design and Plan: Description
The research ‘s overall study plan and design (configuration) (e.g., parallel, cross-over) should be briefly but clearly defined, using charts and diagrams as appropriate.
If a somewhat similar protocol has been used in other 7 studies, it may be helpful to mention this and explain any major variations.
Appendix 16.1.1 will contain the actual protocol and any modifications as well as a sample case report form (only single pages; i.e., it is not appropriate to include similar pages from the forms for various assessments or visits) as Appendix 16.1.2. If any of the information in this section comes from sources other than protocol, it is important to classify those.
- 9.2 Discussion of Study Design, Including the Choice of Control Groups:
As required the basic control selected and the study design used should be addressed. Following are examples of concept problems that would attract discussion.
Usually, known control (comparison) classes are placebo concurrent control, no concurrent control of treatment, active concurrent control of treatment, concurrent control of the dose comparison, and historical control.
- 9.3 “Selection of Study Population
- 9.3.1 Inclusion Criteria
- 9.3.2 Exclusion Criteria
- 9.3.3 Removal of Patients From Therapy or Assessment
- 9.4 Treatments
- 9.4.1 Treatments Administered
- 9.4.2 Identity of Investigational Products(s)
- 9.4.3 Method of Assigning Patients to Treatment Groups
- 9.4.4 Selection of Doses in the Study
- 9.4.5 Selection and Timing of Dose for Each Patient
- 9.4.6 Blinding
- 9.4.7 Prior and Concomitant Therapy
- 9.4.8 Treatment Compliance
- 9.5 Efficacy and Safety Variables
- 9.5.1 Efficacy and Safety Measurements Assessed and Flow Chart
- 9.5.2 Appropriateness of Measurements
- 9.5.3 Primary Efficacy Variable(s)
- 9.5.4 Drug Concentration Measurements
- 9.6 Data Quality Assurance
- 9.7 Statistical Methods Planned in the Protocol and Determination of Sample Size
- 9.7.2 Statistical and Analytical Plans
- 9.7.2 Determination of Sample Size
- 9.8 Changes in the Conduct of the Study or Planned Analyses“
10. STUDY PATIENTS
- 10.1 Disposition of Patients
A list of all patients discontinued from the study after enrollment should also be given in Appendix 16.2.1, broken down by center and treatment category, giving a patient name, particular reason for discontinuation, medication (drug and dosage), total dose (if applicable), and period of care prior to discontinuation.
- 10.2 Protocol Deviations
In Appendix 16.2.2, individual patients with these protocol deviations should be listed, broken down by the center for multicenter studies
11. EFFICACY EVALUATION
- 11.1 Data Sets Analyzed
A tabular listing of all patients, visits and findings should be made, apart from the efficacy review given in Appendix 16.2.3 (see for example Annex VI). The reasons for exclusion are also to be evaluated over time for the entire patient population (see for example Annex VII).
- 11.2 Demographic and Other Baseline Characteristics
The critical variables will depend on the specific nature of the disease and on the protocolbut will usually include:
Demographic variables: – Age – Sex – Race
Disease factors:
- Specific (if not uniform) entry requirements, length, stage and severity of disease, and other specific use or established prognostic importance clinical classifications and subgroupings.
- Baseline values for vital clinical tests that were performed during the study or identified as essential markers of prognosis or therapy response.
- Concomitant disease upon initiation of the trial, such as kidney disease , diabetes, heart failure.
- Prior illness relevant.
- Related previous diagnosis in the study for the illness treated. Concomitant treatment continued, even though the dosage was changed during the study, including oral contraceptive treatment and hormone replacement therapy; therapy stopped at the start of the research period (or changed during the research).
Other factors that may affect response to therapy (e.g., weight, renin status, antibody levels, metabolic status).
Other possibly relevant variables (e.g., smoking, alcohol intake, special diets) and, for the women, menstrual status and date of last menstrual period, if pertinent for the study.
In addition to tables and graphs including group data for these baseline variables, specific individual patient demographic and baseline data, including laboratory values, and all concurrent drugs for all randomized individual patients (broken down by care and multicenter research center) should be provided in Appendix 16.2.4 of the by-patient tabular lists.
- 11.3. Measurements of Treatment Compliance
- 11.4 Efficacy Results and Tabulations of Individual Patient Data
- 11.4.1 Analysis of Efficacy
- 11.4.2 Statistical/Analytical Issues
The statistical analysis used should be described for the clinical and statistical reviewers in the text of the report, with detailed documentation of statistical methods (see Annex IX) presented in Appendix 16.1.9.
- 11.4.2.1 “Adjustments for the Covariates
- 11.4.2.2 Handling of the Dropouts or Missing Data
- 11.4.2.3 Interim Analyses and Data Monitoring
- 11.4.2.4 Multicenter Studies
- 11.4.2.5 Multiple Comparisons/Multiplicity
- 11.4.2.6 Use of an “Efficacy Subset” of the Patients
- 11.4.2.7 Active-Control Studies Intended to Show Equivalence
- 11.4.2.8 Examination of the Subgroups
- 11.4.3 Tabulation of the Individual Response Data
- 11.4.4 Drug Dose, Drug Concentration, and Relationships to the Response
- 11.4.5 Drug-Drug and Drug-Disease Interactions
- 11.4.6 By-Patient Displays
- 11.4.7 Efficacy Conclusions“
12. SAFETY EVALUATION
The ICH Guideline entitled “Clinical Safety Data Management: Definitions and Standards for Expedited Reporting” defines serious adverse events as follows:
“A significant adverse event (experience) or reaction is any medical incident that at any dose: results in death, is life-threatening, needs hospitalization or prolongation of current hospitalization, results in permanent or severe disability/incapacity or is a congenital anomaly/birth defect.”
In the following sections, three kinds of analysis and display are called for:
1. Summarized data, often using tables and graphical presentations presented in the main body of the report;
2. Listings of individual patient data; and
3. Narrative statements of events of particular interest.
- 12.1 “Extent of Exposure(Duration, Dose, Drug concentration)
- 12.2 Adverse Events
- 12.2.1 Brief Summary of Adverse Events
- 12.2.2 Display of Adverse Events
- 12.2.3 Analysis of Adverse Events
- 12.2.4 Listing of Adverse Events by Patient“
All adverse effects for each patient should be mentioned in Appendix 16.2.7, including the same case on multiple occasions, giving both preferred term and original term used by the investigator. The list should be by investigator and category of care, which should include:
- Patient identifier.
- Age, race, sex, weight (height, if any).
- Location of the case report forms, if provided. The adverse event (preferred term, reported term).
- Duration of the adverse event.
- Severity (e.g., mild, moderate, severe). Seriousness (serious/nonserious).
- Action taken (none, dose reduced, treatment stopped, specific treatment instituted, and so forth). Outcome (e.g., CIOMS format).
- Causality assessment (e.g., related/not related).
- How this was determined should be described in the table or elsewhere.
- Date of onset or date of clinic visit at which the event was discovered.
- Timing of onset of the adverse event in relation to the last dose of the test drug/investigational product (when applicable).
- Study treatment at the time of event or the most recent study treatment taken. Test drug/investigational product dose in absolute amount, mg/kg or mg/m2, at time of event.
- Drug concentration (if known).
- Duration of test drug/investigational product treatment.
- Concomitant treatment during study
- Any abbreviations and codes should be clearly explained at the beginning of the listing or, preferably, on each page.
12.3. Incidents, Other Serious Adverse Events, and Other Notable Incidents in Adverse Events, Other Moderate Adverse Events, and Other Critical Adverse Effects warrant special consideration.
- 12.3.1 For the following incidents, the summary of Deaths, Other Serious Adverse Incidents and Other Important Adverse Events Listings, containing the same details as called for in section 12.2.4, should be given.
Listings, containing the same information as called for in the section 12.2.4, should be provided for the following events.
- 12.3.2 Death accounts, other serious adverse events, and several other significant adverse events
Please provide the following information: Patient Identifier. Patient age and sex; general health condition, if applicable. Test drug / research product administered; dosage of medication, if this differed among patients; and length of time given.
- 12.3.3 Analysis and Discussion of the Deaths, Other Serious Adverse Events, and Other Significant Adverse Events
- 12.4 Clinical Laboratory Evaluation
- 12.4.2 Evaluation of Each Laboratory Parameter
- 12.4.2.1 Laboratory Values Over Time
- 12.4.2.2 Individual Patient Changes
- 12.4.2.3. Individual Clinically Significant Abnormalities
- 12.5. Vital Signs, Physical Findings, and Other Observations Related to Safety
- 12.6 Safety Conclusions
13. DISCUSSION AND OVERALL CONCLUSIONS
The study’s effectiveness and safety findings and the risk-benefit relationship should be summarized and addressed briefly, referring as needed to the tables , figures and sections above. The presentation does not necessarily replicate performance explanations or add new outcomes.
14. TABLES, FIGURES, AND GRAPHS REFERRED TO BUT NOT INCLUDED IN THE TEXT
Figures should be used in order to visually summarize the important results, or to clarify results that are not easily understood from tables.
Significant demographic, efficiency, and safety data should be provided in the text of the report in summary figures or tables.
Moreover, if these are obtrusive due to size or number they should be listed here, cross-referenced to the document, along with supporting, or supplementary, statistics, charts, or lists.
The following information may be presented in this section of the core clinical study report:
- 14.1 “Demographic Data Summary figures and tables.
- 14.2 Efficacy Data Summary figures and tables
- 14.3 Safety Data Summary figures and tables
- 14.3.1 Displays of the Adverse Events
- 14.3.2 Listings of the Deaths, Other Serious and Significant Adverse Events
- 14.3.3 Narratives of the Deaths, Other Serious and Certain Other Significant Adverse Events
- 14.3.4 Abnormal Laboratory Value Listing (each patient)“
15. REFERENCE LIST
A list of articles from the literature pertinent to the evaluation of the study should be provided.
Copies of important publications (Appendices 16.1.11 and 16.1.12) will be included in an Appendix. In accordance with the internationally agreed standards of the 1979 Vancouver Declaration on “Uniform Requirements for Manuscripts Submitted to Biomedical Journals” or the system used in “Chemical Abstracts,” references should be given.”
16. APPENDICES
This section should be prefaced by the full list of all Appendices available for the study report.
Where allowed by the regulatory authority, some of the following Appendices do not need to be submitted with the report but should only be submitted on request.
Therefore, the applicant should clearly indicate those Appendices submitted along with the study.
To have Appendices available on request they will be completed by the time the application is submitted.
- 16.1 Study Information
- 16.1.1 Protocol and protocol amendments.
- 16.1.2 Sample case report form (unique pages only).
- 16.1.3 List of IEC’s or IRB’s (plus committee chair name if needed by regulatory authority) and representative written information for forms of consent for patients and sample consent.
- 16.1.4 List and summary of investigators and other significant participants in the research, including brief (one page) curriculum vitae or equivalent summaries of training and experience relevant to clinical study results.
- 16.1.5 Signatures of responsible medical officer of principal or coordinating investigator(s) or sponsor, depending on the provision of the regulatory authority.
- 16.1.6 List of patients taking study drug(s)/research product(s) from different batches where more than one lot has been used.
- 16.1.7 Scheme and codes for randomisation (assigned to patient recognition and treatment).
- 16.1.8 Certificates of inspection (if available).
- 16.1.9 Documentation of the processes used.
- 16.1.10 Documentation of methods for inter-laboratory standardization and procedures for quality assurance where used.
- 16.1.11. The Study-based publications.
- 16.1.12 Significant publications which are listed in the study.
- 16.2 Listings of patient info.
- 16.2.1 Patients Discontinued.
- 16.2.2 Deviations from protocol.
- 16.2.3 Patients exempt from consideration of the effectiveness.
- 16.2.4 Human demographics.
- 16.2.5 Data on compliance and/or concentration of drugs (if available).
- 16.2.6 Data on individual efficacy response.
- 16.2.7 Adverse case lists (every patient).
- 16.2.8 Listing by patient of individual laboratory measurements, if necessary by regulatory authorities.
- 16.3. Formulas for a Case Report (CRF)
- 16.3.1 CRFs for deaths, other significant adverse effects and adverse event withdrawals.
- 16.3.2 Other submitted CRFs.
- 16.4 Listings of individual patient info.
https://www.fda.gov/media/71271/download
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