Clinical Researcher—September 2020 (Volume 34, Issue 8)

PEER REVIEWED

Sheryl Stewart, MCR, CCRP

The tenets of Good Clinical Practice (GCP), promulgated by the International Council for Harmonization (ICH), require that investigator-initiated trials (IITs), especially those involving an Investigational New Drug application to the U.S. Food and Drug Administration (FDA), have the principal investigator (PI), the institution, and the study team assume roles of both the sponsor (ICH GCP E6(R2), Section 5) and of the PI (ICH GCP E6(R2), Section 4).{1} If you are part of an IIT team, whether you are the investigator, a clinical research coordinator, or someone working in any of the many other important roles within the team, you may be tasked with authoring a clinical study report (CSR) at one time or another within the course of the study. At the very least, you may be asked to contribute to, or provide peer review of the document before it is submitted for its intended purpose.

The purpose of this review is to provide a framework for study team members, whether it’s for a large team that includes regulatory and administrative support or for smaller teams with only one or two members, for writing and organizing the CSR.

Background

First, is important to understand the definition, requirements, and potential uses of a CSR. The report is a comprehensive look at all the data produced in a clinical study, presented in text, tables, and figure formats. It will often include discussions and conclusions that provide context to the findings regarding the drug, device, biological product, surgical method, counseling practice, or any other type of therapeutic product or practice under study and where it may contribute to an improvement on the state of the art for treating or preventing a particular health condition.

If a study has prespecified endpoints or parameters, the CSR will report the current outcomes and statistical parameters for these endpoints. Key messages will be referred to and highlighted throughout. Key messages are important study findings that support the prespecified endpoints, supply proof of the justification of clinical benefit, or differentiate the study product from others in the therapeutic space.

Most likely you already appreciate the ethical responsibility a clinical study team has to clinical study data transparency, which for that reason alone would make the production of some sort of CSR necessary. Indeed, the preparation and representation of study progress is prescribed in the aforementioned ICH GCP E6(R2) guideline,{1} which states that study sponsors should ensure that clinical trial reports are prepared and provided to regulatory agencies as they are required.

Further, the guideline recommends study sponsors to rely on a subsequent guideline on Structure and Content of Clinical Study Reports (ICH E3).{2} Lastly, adhering to this ethical responsibility and following GCP have become mandated both in the U.S. and in Europe, where study data are expected to be recorded on ClinicalTrials.gov and the EudraCT database, respectively, for the sake of transparency and in support of further scientific inquiry, thus making the organization and preparation of study data in a prespecified format necessary.{3,4}

There are a few different uses for a CSR, though primarily it is utilized either to summarize the data and outcomes at the end of the study, or for marketing authorization. Those two purposes are specifically outlined in ICH E3 and ICH E6.{1,2} However, a CSR may also be written for third-party payer reimbursement purposes, providing details in support of clinical benefit. Because in most cases CSRs will ultimately have a regulatory reviewer, authoring a report that is consistent in formatting and content with what is expected will hopefully not only enable a smooth review, but also will facilitate proper data cleaning, presentation, and timeliness that make the document fit for purpose.

Templates

ICH E3 offers a CSR template to guide you in terms of providing the proper data and content in a specified order and format. This guideline can be found either on the ICH website or the FDA website.{2,5}

It is important to note that there are no requirements to follow the template precisely. Not every section is appropriate for every study, and because the overarching purpose of a CSR is to provide proper representation of the study data and any key messages you want to report, flexibility is allowed and encouraged in order to meet those important goals. However, for anyone new to the process of crafting a CSR, this template is a helpful starting point.

Transcelerate Biopharma, a nonprofit organization involved in researching means to increase efficiency and innovation in the pharmaceutical research sciences, also has interpreted the ICH template and has produced a useful tool to improve this reporting.{6} If the instruction and guidance in the ICH or Transcelerate templates do not meet your needs, or you have further questions as to how to properly represent the study data, the CORE reference manual (Clarity and Openness in Reporting E3-based) is another resource. It was produced in 2016 in response to regulatory changes for public disclosure of clinical study data, and can provide direction and interpretation of the ICH E3 template.{7}

For the novice author of a CSR, however, the ICH E3 template, coupled with the Transcelerate template, should provide a strong starting point for the project planning of the report, as well as the document formatting.

Sidebar: Tips and Tricks for Getting Started

· Review the template sections and start collecting the necessary documents you’ll need to review and refer to in the document, such as the protocol, investigator brochure, monitoring plan, and the statistical analysis plan.

· Create a Microsoft^TM (MS) Word document using template headings and list levels to help organize your thoughts about the project, draft the initial outline of the document, and to plan next steps in collecting information.

If MS Word is not a strong skillset for you, consider taking a MS Word course. There are many helpful online courses to assist with formatting, captions, redlining, pagination, headers/footers, etc.

· Save document with an additional backup on the computer and in a cloud-based, secure file with limited access.

Determining Stakeholders

Once you’ve reviewed the template and created a draft outline of the project, determine the key stakeholders with whom you’ll need to partner to complete this project. Likely you will need input from your clinical study management team, teammates responsible for data entering and cleaning, a biostatistician, any teammate or organization member able to perform literature reviews, those staff qualified to compose patient or adverse event narratives, and those team members who can help determine key messaging in this report. Lastly you will want to determine the group of key stakeholders who will be your final review team for the document—those who will help you finalize the document prior to submission.

Sidebar: Tips and Tricks for Stakeholder and Project Management

· Identify the stakeholders for each section of the template per section (statistician, data management team, content experts).

· Collect and review resources, including any previous study publications, presentations, or reporting for any key messaging about the study drug, similar drugs, or the disease under study.

· Consider drafting a project charter or scope document to ensure commitment from all required teammates on scope, deliverables, and timelines.

Determining Timelines

Once you have determined your key stakeholders, you will want to determine timelines to ensure steady progress continues to be made on the document. If you’ve chosen to utilize a scope document, you’ll want to include these timelines in it, so the entire team is aware of the project process, the timing requirements, and each gating item (key gating items are summarized in Figure 1).

Figure 1: Preparing, Writing, and Review of the Clinical Study Report—Key Gating Items

Preparation of Data	Writing and Document Review
o Data cleaning and query resolution	o Write non-results sections
o Plan tables, listings, and figures (TLFs)	o Perform literature review
o TLF creation and revisions	o Write results sections
o TLF editing	o Cross team/stakeholder review
o Data-lock process	o Incorporation of revisions
o Final TLF preparation	o Finalize report for submission

Time management is paramount for clinical trial submissions to regulatory authorities. Attendees at medical writing conferences over the course of a five-year period (2008 to 2013, n=78) were surveyed to determine to how long each step of the CSR process can typically require.{8}

To complete a “moderately complex” CSR for a Phase III study with 200 to 400 participants, the surveyed medical writers responded with a mean answer of 16.9 days from the receipt of the final tables, listings, and figures (TLFs) to delivery of the first draft of the CSR. They estimated a mean of 25.7 days from the first draft to the final draft routed for review. The time from database lock to completion was reported to be on average 83 days.

While there was a wide range for the timelines reported, these data provide the novice CSR author a basic reference point for how long the individual processes can expect to take with experienced medical writers. Fortunately, while TLFs are being crafted, multiple other “Writing and Document Review” tasks from Table 1 can be performed simultaneously.

At Last…the Writing!

Typically, the flow of your CSR will progress under six primary headings or sections, not unlike those used in a research manuscript. On the front end, even before the background and introduction, the document will include a title page, synopsis, table of contents, list of abbreviations, ethics statements, and details on the study’s administrative structure. The primary sections to come after that are highlighted in Figure 2 and summarized in turn below.

Figure 2: Primary Sections

Background, Intro. > Non-Results > Results > Discussion > Conclusion > Exec. Summary

Background and Introduction

When available, utilize any state-of-the-art analysis of the product/therapy from the protocol for your CSR introduction. If not available, you can briefly summarize the study design, objectives, and population and then you’ll need to craft a novel but brief state-of-the-art analysis based on literature review.

Be sure to align with the key messaging of your study and the indications of your study drug, device, or other type of therapeutic product or method. Utilize good literature review practices, such as choosing peer-reviewed publications, editorials from key opinion leaders in the therapeutic area, and studies with large or randomized cohorts, for support. This section will likely be no longer than one page.

Non-Results Section

Whether to cut and paste the procedures and assessments, primary and secondary endpoints, parameters or hypotheses, planned statistical analyses, monitoring plans, adverse event definitions, and assessment rules directly from the protocol or to simply refer to the protocol and the other study documents in an appendix is a topic of debate amongst medical writers of CSRs. Keep in mind that the CSR should be able to stand alone as a document, and thus while it is important to keep the document concise, it must be comprehensive enough for the reader to understand the study design, objectives, endpoints, processes, and intended analyses without having to refer constantly to the protocol. Regardless, in any summary of the study design, processes, and endpoints, be sure to align with any previously utilized language for consistency across study documents.

Results Section

Using the template and your tables as your structure, summarize the data and pull out any signals and trends, aligning with key messaging where possible. Start with patient disposition and demographics as per the template. Note any protocol deviations that may or may not have impacted patient safety or the evaluation of the outcomes.

Assess and evaluate the study outcome results against primary endpoints and secondary endpoints before discussing any additional secondary outcomes. You should not simply restate the data in the tables; however, refer to specifics in the tables when summarizing.

If you find that you cannot make a statement or conclusion given the TLFs you have, or you are consistently having to perform your own math to support your statements, consider asking your biostatistician to create the tables that will represent the data in a way that will better support your statement. For instance, it is acceptable to state that “most” of the patients responded to the study drug if more than 50% did so; however, if you are having to consistently add up percentages in a table to be able to state, for example, that 77% of the patients responded in a certain way and 33% responded in another, then you should have the biostatistician reformat the data output so it represents the percentages you want to report.

Patient narratives are an important source of context for the reader of the CSR. Depending on your study, you may need to collaborate with either your teammates responsible for assessment of adverse events or the study database administrator to help generate patient and/or event narratives for the CSR. If tasked with compiling or editing patient narratives yourself, the ICH E3 guideline prescribes the necessary components of a comprehensive patient safety narrative (Section 12).{2}

Narrative writing advice has also been previously published and would be a helpful source of direction for the novice narrative writer.{9,10} Narratives are suggested for every patient who experienced a safety endpoint event or death during the course of the study. Tie in patient narratives where appropriate when discussing safety events or refer to the patient narrative section when highlighting a particular patient’s data.

Discussions and Conclusions

Discussion and conclusion sections can either be placed after each section or placed at the end of the document. They should not simply restate the previous table summaries, but provide context and align the results with key messaging. Use an evidence-based approach, including literature references to provide more context as to the nature of the study outcomes with respect to the state of the art for the product/therapy, outcomes from alternate approaches, or further justification of clinical benefit with regard to potential disease progression. The conclusion section at the end of the document is often in bulleted format—not only for ease of the reader, but also to clearly highlight the key messaging and important outcomes you wish to impart.

Executive Summary

The executive summary, while placed at the front of the document prior to the introduction, is often easiest to construct last, as an overall summary of the entire document. The key elements of this summary should briefly recap the study design and objectives. Most likely only the primary and secondary endpoints should be included, unless additional outcomes proved compelling and important within the course of the study. Refer to any important literature comparisons as they relate to any conclusions made about the success or outcomes of the trials. Conclude the executive summary in a similar fashion to the overall study conclusion.

Sidebar: Tips and Tricks for the CSR Writing Process

· Create all headings and/or multilevel lists before you start writing.

· Request a “soft” database extract and a pre-run of the TLFs.

Often this first quick look at the TLFs will reveal any discrepancies in data entry or queries that can then be resolved before the TLFs undergo the larger review process.

· Begin a rough draft of the results sections from these early tables. Though some changes in the data will likely occur, most data will stay the same and key messages will remain valid, thus you can get a head start on the document while waiting for final tables.

· Insert TLFs without captions until you are sure you will not be updating or switching out tables.

· Wait until the end of the review process to:

Create any hyperlinks

Finalize your table of contents and table of figures

Insert your bibliography

Insert your listings and appendices

Review Process

The review process can either facilitate a better document or it can slow down the entire process. The purpose of a cross functional review of a CSR is to confirm accurate key study messaging and data; allow medical review of the patient narratives, outcomes, and conclusionary statements; review the logical flow of ideas; and ensure that the CSR language is consistent across any other study document (i.e., the protocol, statistical analysis plan, etc.).

Sidebar: Tips and Tricks for an Efficient Review Process

· Request reviewers to initially review for content, as errors in formatting, grammar, and spelling are fine to notate, but are much less important (and likely will be caught later) than providing content review.

· Start the review team working on the non-results section first and finalize it before sending them the results section.

· Discourage the review team from backtracking to the non-results section, as it should be considered finalized unless something major changes.

· Maintain the documents for review in a secured, shared, cloud-based content management application, such as Box.com, so reviewers can review and provide revisions in real time with each other and avoid version confusion.

Conclusion

CSRs are required by regulatory authorities to report and summarize the outcomes of a clinical study. Pre-project stakeholder determination and timeline planning can help with project management. Templates contained with the ICH E3 guideline can help organize the project as well as help create and finalize a document that is fit for purpose and meets the content expectations of the regulatory reviewer.

References

ICH Working Group. 2016. ICH HARMONISED GUIDELINE INTEGRATED ADDENDUM TO ICH E6(R1): GUIDELINE FOR GOOD CLINICAL PRACTICE E6(R2).
ICH Working Group. 1995. ICH HARMONISED TRIPARTITE GUIDELINE: Structure and Content of Clinical Study Reports E3.
U.S. Department of Health and Human Services. 2016. Clinical Trials Registration and Results Information Submission, 42 CFR Part 11. https://www.federalregister.gov/documents/2016/09/21/2016-22129/clinical-trials-registration-and-results-information-submission
European Commission. 2001. Letter to Stakeholders Regarding the Requirements to provide results for Authortied clinical trials in EUDRACT. In: Article 57(2) Regulation (EC) No 726/2004 and Article 41(2) of Regulation (EC) No 1901/2006. https://eudract.ema.europa.eu/
U.S. Food and Drug Administration. 2018. ICH Guidance Documents. https://www.fda.gov/science-research/guidance-documents-including-information-sheets-and-notices/ich-guidance-documents
Transcelerate Biopharma Inc. Clinical Template Suite (CTS), Template, Resources, and Use Guidance. https://transceleratebiopharmainc.com/assets/clinical-content-reuse-assets/
Hamilton S, Bernstein AB, Blakey G, et al. 2016. Developing the Clarity and Openness in Reporting: E3-based (CORE) Reference user manual for creation of clinical study reports in the era of clinical trial transparency. Research integrity and peer review. 1:4.
Hamilton S. 2014. Effective authoring of clinical study reports. Medical Writing 23(2).
Nambiar I. 2018. Analysis of serious adverse event: Writing a narrative. Perspect Clin Res 9(2):103–6.
Ledade SD, Jain SN, Darji AA, Gupta VH. 2017. Narrative writing: Effective ways and best practices. Perspect Clin Res 8(2):58–62.