How to Create Fit-For-Purpose Clinical Study Reports for Successful Submissions

Editor's Notes

• #6: Within a Clinical Drug Program, every study that was conducted in humans with the study drug must be summarized in a CSR. optional from EU reg we can add that "the applicant for marketing authorization shall submit to the EU database the clinical study report within 30 days after the day the marketing authorisation has been granted, the procedure for granting the marketing authorisation has been completed, or the applicant for marketing authorisation has withdrawn the application." Source: CSR overview training https://mmsholdings.sharepoint.com/:p:/r/hr/_layouts/15/doc2.aspx?sourcedoc=%7BEEF8C96C-2A66-4E52-8E7C-B23DDEC1BF5B%7D&file=CSR%20Overview.pptx&action=edit&mobileredirect=true&cid=d31f577c-e28a-4ee7-9f0d-1cfc01be7248
• #7: CSR is ultimately a component of the regulatory submission for the marketing applications, used across EU, Japan, and the US every study that was conducted in humans with the study drug must be summarized in a CSR. The CTD is organized into 5 modules, module 1 is region specific and modules 2-5 are intended to be common for all regions CTD [common technical document] = is a set of specifications for application dossier for the registration of medicines and designed to be used across Europe, Japan and the United States. The CSR is ultimately a component of the regulatory submission (ie, Common Technical Document [CTD]) for the registration of medicines, used across EU, Japan, and the US. Module 5 of CTD: includes all individual CSRs Module 2.7.3 of CTD (Summary of Clinical Efficacy): includes a short study narrative Module 2.7.6 includes the CSR Synopsis
• #8: Regional Regulatory guidance for CSR format and content allows flexibility depending on the type of study and submission These guidances or guidelines are not requirements, but assist sponsors in the development of a report that is complete, free from ambiguity, well organized and easy to review that will assist with successful submission ICH Efficacy 3 structure and content of clinical study reports (1996) and E3 Q&As Provides a recommended template for full CSR and guidance for content indicates that the recommended full format can be abbreviated for certain studies such as studies that are not pivotal for claiming effectiveness or when a study is discontinued early (as will be expanded on in the next section of this webinar). but does not provide a description of the content FDA guidance for industry – submission of abbreviated reports and synopses in support of marketing applications (1999) Is the only regulatory document that outlines when the abbreviated or synoptic format is acceptable and which sections can be included, depending on the role of the CSR within the regulatory submission EMA Note for Guidance on Structure and Content of Clinical Study Reports does not provide further guidance on abbreviated or synoptic formats Additional guidances are available for the appendices to be included per format and content of CSRs, but will not be discussed in this webinar. Types of CSR templates and how to use it – fit for purpose Not just a one size fit all – it can be indicated based on phase of trial, timing of trial and content
• #9: In the FDA guidance, a general overview is provided to help in determining the types of studies to be submitted and its roles in the submission This helpful decision tree indicates the 3 main recommended formats that can be adapted based on the study types or submission needs. Selection of the correct format is critical for effective communication and authoring and a successful submission. I will now hand over to Michelle who will expand on selecting and tailoring a CSR format Case Report Tabulation (CRT) is the collection of the annotated case report form (CRF)
• #11: Many different titles applied to CSRs that can be confusing – full, final, supplemental, abbreviated, etc. Selection of what type of CSR to prepare depends on characteristics of the study CSR template Types of CSR templates and how to use it – fit for purpose. Not just a one size fit all Tailor CSR template according to study – phase, timing of CSR relative to study completion Other considerations for less common study types Note: Names and definitions for the types of CSRs may not be uniform across clients Select most efficient option – saves time and effort (money)
• #12: Although ICH E3 is mainly aimed at efficacy and safety trials, the basic principles and structure described can be applied to other kinds of trials, such as clinical pharmacology studies. Depending on the nature and importance of such studies, a less detailed report might be appropriate. Full CSR – all ICH E3 sections included (Sections 1 through 16). MMS smartstart template or other transcelerate-based templates do not have same section numbering as ICH but have information in the same general location in document. Also very lean, so can be used for abbreviated/synoptic purposes Abbreviated CSR – Certain sections are omitted, resulting in a shorter document…, can be a separate template or a modified version of the Full Synoptic CSR/Synopsis – condensed version of the CSR… (mention synopsis CSR is not the same as CSR synopsis which is Section 2 of the CSR) can be a separate template or a modified version of the Full Studies that do not contribute to the evaluation of the effectiveness of a product for a specific indication can be submitted as either abbreviated reports or synopses.
• #13: *animate – each column to appear on its own (can just be a white box that disappears over abbreviated, then synoptic Full CSR All studies designed to support an efficacy claim for the dose, regimen, population, or indication All sections of template, following ICH organization (or in a Legacy format depending on start date of study) Summarize the data and outcomes at the end of the study, or for marketing authorization Can be used for a ‘final’ or ‘interim’ report Used for any studies any studies contributing to the evaluation of efficacy Abbreviated CSR Any study not intended to support the efficacy claim for the dose, regimen, population, or indication. A full description of safety aspects should always be included. Summary of data, omits certain CSR sections, abbreviated methods and efficacy, comprehensive safety Condensed version of full CSR Unrelated or aborted study Used for studies are not intended to contribute to the evaluation of efficacy but still need to be submitted to support safety or to show that they don't cast doubt on efficacy Synoptic CSR Any study not relevant to the evaluation of efficacy but needed for full evaluation of safety Summary of disposition/PK/clinical pharmacology/efficacy data, complete safety Usually no in-text tables unless study/reference drugs or SAEs need a table Efficacy not relevant application Used for studies not intended to support safety or efficacy, but data is still required in order show that it doesn't cast doubt on the safety claims submitted/supported in the application https://www.fda.gov/regulatory-information/search-fda-guidance-documents/submission-abbreviated-reports-and-synopses-support-marketing-applications Https://www.mmsholdings.com/navigating-the-four-types-of-clinical-study-reports/ Can summarize/omit efficacy data in some circumstances, but safety data needs to be complete
• #14: Modifications to template based on attributes of the trial: Phase of Clinical Trial Phase 1 – PK/PD Phase 2 – dose ranging, placebo controls Phase 3 – lengthy safety discussion, special safety, events of interest Phase 4 – postmarketing Timing Relative to Study Completion Date Primary/Interim (before study completion date, uses database cutoff) Final (after study completion date) Supplemental/Addendum (complements previous reports) Other characteristics of study Subpopulation analyses
• #15: Full template can be modified as needed to fit study – speak to template flexibility to meet study and submission needs Phase 1 – typically focus on PK/PD, small population size (healthy volunteers or patients). Phase 2 – Safety and methodology, which could include dose-finding for further Phase 2 or Phase 3 studies. Phase 3 – Efficacy and safety. May also include noninferiority with existing treatments Phase 4 – postmarketing data The Protocol, which establishes the phase of the study, and the design of the study often drive the type of CSR written (template) as well as the content of the CSR
• #16: Considerations around PCD – before or after Schema showing IA, PCD, LSLV, LTFU safety The type of a CSR can be based on the timing relative to reporting primary endpoint analysis: Interim = predetermined early analyses, written before primary endpoint analysis or LSLV using a database cutoff, provides a full description of the primary endpoints but not the secondary/long-term analyses. Final = triggered by primary endpoint analysis and/or LSLV Supplemental/Addendum = written after primary endpoint analysis and/or LSLV to complement primary/previous reports. The 3 types of template formats (full, abbreviated, synoptic) can be adapted depending on the type and amount of data. For example: A “Full” format can be used for a Final report where all the analyses are included or for an interim CSR that uses a data cutoff date An “Abbreviated” or “Synoptic” format can be used for a Final or Supplemental/Addendum report that only report partial data not described previously.
• #17: Subreports may be preplanned or ad hoc/post hoc
• #18: Subreports may be preplanned or ad hoc/post hoc
• #20: We think of the CSR as a stand-alone document, but it is an integral part of the submission. When you prepare for authoring a CSR start with the end in mind. Understanding the study and its role in the submission will help you “tailor” your CSR for a successful submission. Some examples of questions to ask up front that will enable the authoring team to choose the appropriate CSR format that is compliant with regulatory guidelines and to present the content with a focus on the key analyses and results. Will the CSR support the efficacy claim for the dose, regimen, population, indication, or a related indication? - Abbreviated reports using summarized data or with some sections deleted, may be acceptable for studies not designed to establish efficacy for the claim submitted Where will the CSR be submitted? - Will it be submitted in support of a marketing application (NDA or MAA)? Regulatory agencies may have different requirements for the title page or certain appendices that include regional information. For submission to the EU, CSRs have to be compliant with the EU CTR (with respect to requirements for disclosure of personal data and company confidential information) Is the study complete, ongoing, or was it discontinued? - This affects the data presented in the report whether it is final study data or interim data as of a certain data cutoff date. A study can be discontinued due to efficacy, safety or feasibility. If the study was terminated early a full report is generally not necessary. What are the primary endpoints/analyses in this study? - Is the focus on efficacy, safety for the primary analysis or is this a PK/PD/BA/BE study? Were any data from this protocol presented in a previous report? - It is important to know whether all the data collected will be described in the CSR or only supplemental data since the previous report. On the next slides we will see some scenarios of how to use the FDA decision tree to choose the fit-for-purpose CSR format based on study attributes.
• #21: Study is well controlled and evaluates the effectiveness of the product for the indication for which a marketing approval is sought, therefore a full report should be submitted.
• #22: Other considerations for Full CSRs All ICH E3 sections are required following ICH E3 structure or Trancelerate-based template (s.a. SmartStartTM). Full study reports (i.e., the complete ICH E3 report) present a comprehensive clinical and statistical description of the study conduct, along with efficacy and safety data. The procedure to maintain the blinding when interim analyses are performed should also be explained. A full report should be used for the description of interim analysis data up to the cutoff date to present primary/final efficacy data and interim safety data. A supplemental CSR will have to be written for the additional data after LSLV; it will not repeat the data from the first report but will refer to it.
• #23: The study is not intended to contribute to the evaluation of product effectiveness for the indication for which a marketing approval is sought, therefore an abbreviated report should be submitted.
• #24: Other considerations for Abbreviated CSRs The abbreviated study report should contain only selected sections of E3. Certain sections and appendices can be omitted. Efficacy information should be concise and suggested to be primarily in table form (enough information to allow the reviewers to assess whether the efficacy results cast doubt on the effectiveness of the product for the proposed indication). There should be enough detail of design and results to allow the regulatory authority to determine whether a full report is needed. An abbreviated report should contain a full report of information related to safety.
• #25: Study has defect (in design, conduct data handling or analysis) that renders it incapable of supporting a useful and/or relevant conclusion, therefore a synoptic report should be submitted.
• #26: Other considerations for Synoptic CSRs A synoptic report should contain sufficient information to allow the reviewer to assess if the results cast doubt on the safety of the product for the proposed indication. A summary of the study disposition, PK, PD, and efficacy data should be provided. A complete discussion of the safety data including all information from section 12 (Safety Evaluation) as described in ICH E3 should be included. In some cases, with the agreement of the appropriate reviewing division, a complete discussion of safety may not be necessary. Generally, no in-text tables unless SAEs need a table, and no section numbering. May follow ICH E3 synopsis format (Section 2 of the Full CSR). The study protocol and protocol amendments (Section 16.1.1 of ICH E3) should be provided along with the synopsis.
• #28: CSRs can be categorized based on format, study status and other study characteristics. The full CSR format can be modified depending on the type of study and its role in the submission. According to the nature and importance of the study, a less detailed report such as abbreviated or synoptic format might be appropriate. Sponsors should discuss the planned report format and study data presentation and analyses with the reviewing authority at the earliest possible time (for example during the pre-IND or pre-NDA meeting). The goals would be to limit study reporting to that which is essential to document the evidence of effectiveness, and to minimize the need for agencies to request full study reports or additional data for studies originally reported in abbreviated or synopsis format.