Mastering the art of CSR writing

30 08 2011

A clinical study report (CSR) is a “complete” summary of the safety and efficacy data obtained in a clinical study in patients.  The investigational drug may be a therapeutic, a prophylactic or a diagnostic agent.  A CSR is an “integrated” report since it documents all the information pertaining to a study, including methodology, test article details, patient data and outcome; also attached as appendices are protocol, investigator-related information, sample case report form, tables and figures, statistical methods, statistical reports, etc.

CSRs are generally co-authored, and it’s a team exercise.

An eCTD submission or an FDA marketing application may contain multiple CSRs along with clinical summaries and narratives.

Before attempting to assemble a CSR, it is helpful to go through a checklist of items needed to prepare this document.  Susan Caldwell on her blog Biotech Ink Blot lists 48 pieces of information that should be available to a medical writer to complete the task.

The design of a CSR is very similar to a peer-reviewed manuscript except that its format is based on the ICH-E3 guidelines and the targeted audience is FDA.  ICH-E3 provides a skeleton (template or sections) specifying where each piece of information should go, and the regulatory agency (US FDA, EU, etc.) specifies the format.

The sections of a CSR are:

1. Title page

Title page has the following information:

  • Study title.
  • Name of test drug or investigational product.
  • Indication studied.
  • Brief description. (Optional.  Expand information presented in the title.)
  • Sponsor. (Name and address)
  • Study No. (Sponsor’s protocol identification number, clintrial.gov identifier.)
  • Phase of development.
  • IND No.
  • Study start date. (e.g. date first patient enrolled.)
  • Date of early termination, if any.
  • Study end date. (Date last patient completed.)
  • Name and affiliation of principal or coordinating investigator(s), or sponsor’s CMO.
  • Name and telephone of the person responsible for the study report (e.g., sponsor’s clinical study monitor or manager.)
  • Date of the report. (If there is a previous report for the same study, identify previous version by title [or study number] and date.)

2. Synopsis

This section is generally 3-5 pages long.  The Information from the clinical protocol synopsis forms the bulk of this section, which is adapted for CSR by changing the tense from future to past, adding publications resulting from the study, and adding results and conclusion sub-sections.  The synopsis has the following information:

  • Name of sponsor.
  • Title of the study.
  • Investigators.
  • Study centers.
  • Publications. (If any resulting from the trial.)
  • Study period. (Date first patient enrolled to date last patient analyzed.)
  • Phase of development.
  • Study objectives. (May include a brief introduction.)
  • Methodology.
  • Number of subjects. (Planned and analyzed.)
  • Diagnosis and main criteria of inclusion.
  • Duration of treatment.
  • Test product. (Dose, mode of administration, and batch no.)
  • Reference therapy, if any. (Dose, mode of administration, and batch no.)
  • Criteria for evaluation.
  • Study endpoints.
  • Statistical methods.
  • Summary of results. (Description should contain numeric data in addition to p-values and text.)
  • Conclusions. (Optional; generally is a short paragraph.)

A template of Synopsis in the Annex I of  ICH-E3 can be used to generate a Synopsis document.

Sections 3 to 9 of a CSR, together called “shell,” are taken directly form a clinical protocol.  The “shell” is modified by changing tense from future to past, changing page numbers in the Table Of Contents (Section 3,) and adding information where necessary.  Also note that each section may contain specific sub-sections.

3. Table of content for the individual CSR.

With page number indicating location of various sections, tables, figures, appendices, etc.

4. List of abbreviations and definitions of unusual terms or measurement units.

Abbreviations also need to be spelled out at the first appearance in the text and indicated in parentheses.

5. Ethics

Confirm that the proposed study or subsequent amendments were reviewed by IRB, study was conducted in accordance with the Declaration of Helsinki, and describe how and when patients’ consent was obtained.

6. Investigators and study administrative structure

Briefly describe investigators and their affiliations, monitoring and evaluation committee, statisticians, testing facilities, central laboratory facilities, CROs, etc., involved in the study.

* In Appendix 16.1.4, include investigators’ names, roles and qualifications or resume; list of other people involved in data collection, such as, a nurse, pharmacist, house staff physician; names of author(s) of the report and biostatistician(s).

7. Introduction

One page maximum.  Should describe this clinical trial in a broader context by addressing rationale and aims, target population, treatment, duration and endpoints.  Also included in this section are specific guidelines followed, and outcome from FDA meetings, if material to the study.

8. Study objectives

Describe overall purpose.

9. Investigational plan

Study design (include charts and diagrams, if needed,) treatments, patient population, controls, methods, blinding, randomization and stratification, duration of study, safety and data monitoring committee, and interim analyses, control and placebo groups, known or potential problems associated with study design or control group, selection of study population, inclusion and exclusion criteria, drug and treatments, selection of doses and treatment schedules, blinding, treatment compliance, efficacy and safety variables, appropriateness of measurements, data QA, statistical and analytical plans.

9.8 changes in the conduct of the study or planned analyses

Describe times, reasons, procedures used and implications of such changes.

* In Appendix 16.1.2 include actual protocol, including any amendments, and a sample case report form are included
* If patients received more than one batch of drug, patients receiving each batch are identified in Appendix 16.1.6
* Include detailed description of randomization method, codes, patient identifiers and treatment assignments in Appendix 16.1.7
* Documentation of inter-laboratory standardization methods and quality assurance procedures are included in Appendix 16.1.10

10. Study patients

Clear accounting of all patients who enter the study

10.2 Protocol deviations.

Describe all important deviations related to study inclusion or exclusion criteria, conduct of the trial, patient managements or patient assessment.

* List of patients who discontinue prior to end of study period, along with reasons and other details are included in Appendix 16.2.1
* Individual patients who account for protocol deviations are listed in Appendix 16.2.2, broken down by center for multicenter studies.

11. Efficacy evaluation

Describe data sets analyzed, demographics, baseline characteristics, measurements of treatment compliance, efficacy results and tabulations of individual patient data.

Statistical data is generally a WinNonlin or a SAS output.

11.4.2 Statistical/Analytical issues

Include here any changes in analyses after blind-breaking; handling of dropouts and missing data; interim analyses and data monitoring

11.4.2.8 Examination of subgroups.

11.4.3 Tabulation of Individual Response Data.

Individual response data presented in tables.

11.4.4  Drug dose, drug concentration, and relationships to response

11.4.7 Efficacy conclusions

* Tabular listing of all patients, visits, and observations excluded from the efficacy analysis are provided in Appendix 16.2.3
* Tabular listing of patients’ demographic and baseline data included in Appendix 16.2.4
* Tabular data of patients’ complience measures, including drug concentrations in body fluid included in Appendix 16.2.5
* Detailed documentation of the statistical methods, including minutes of meetings of data monitoring group that led to a change in protocol or early termination provided in Appendix 16.1.9

12. Safety evaluation.

In this section, include the extent of exposure, i.e., dose, duration, number of patients, and drug concentrations in bodily fluids;  adverse events (AEs) and common adverse events, serious adverse events and other significant adverse events.Evaluations are summarized using tables and graphs, a list of individual patient date are included, and narrative statements of events of particular interest are presented in this section; clinical laboratory evaluations; vital signs and other observations related to safety; safety conclusions

AEs are described in the form of a table and includes onset, duration, management and resolution of the adverse event.

* A serious adverse event, as defined by the ICH Guideline, Clinical Safety Data Management: Definitions and Standards for Expedited Reporting, is “a reaction is any untoward medical occurrence that at any dose: results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.”

* Other significant adverse events are defined in ICH-E3 are “marked hematological and other laboratory abnormalities and any adverse events that led to an intervention, including withdrawal of drug treatment, dose reduction, or significant additional concomitant therapy.”

13. Discussion and overall conclusions

Include here safety and efficacy conclusions, risk-benefit relationships, new or unexpected findings, clinical relevance, implications for at-risk populations or future studies.

* Discussion may be skipped if is it is planned to be included in the “integrated summaries,” i.e., the safety and efficacy summaries of the entire dossier.

14. Tables, figures, and graphs referred to but not included in the text

Commonly referred to as TLFs (Tables, Listings and Figures.)  May include figures and tables for demographic, efficacy and summary data.  These data are presented in this section, and cross-references in the text above, to maintain a clean uninterrupted flow of text in sections 11 and 12.

15. Reference list

List of articles pertinent to the evaluation of the study.

Copies of important publications attached in Appendix 16.1.11 and 16.1.12

16. Appendices

Include a preface with full list of all appendices.

*Appendix 16.1.5 includes the signatures of the PI and other investigators, and sponsors.

__

ODDS AND ENDS

  • The margins should be the same on all pages; page numbers,  protocol number and document version should be displayed on all pages in the header or footer section.
  • Note: the sub-sections are only briefly described above.  Full details are in ICH-E3.
  • In certain cases an abbreviated CSR may be enough.
  • One challenge for a medical writer is to understand statistical theories and thus be able to intelligently put the statistician’s output into the CSR document.
  • There is no page limit about the CSR content, but CSR brief  synopsis is usually limited to three pages.
  • A well-written CSR can be easily transformed into a peer-reviewed manuscript.
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3 responses

2 03 2012
Ajay K Malik

This post was citing by SRI Portfolio Management in the article, “Pros and cons for third-party evaluation of SRI investments.”
http://sriportfolio.com/2011/09/19/pros-and-cons-for-third-party-evaluation-of-sri-investments/

23 03 2012
How to Become a Regulatory Medical Writer « pipet2pen

[…]  Learn what is a clinical study protocol and a clinical study report (CSR).  UCSD Extension has a an online Medical Writing program which covers the structure of these […]

18 05 2012

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