Reporting the plan under the template
The methods half of a clinical study report built on the TransCelerate common CSR template is the unnumbered ethics section and Sections 1 to 3, ending with the investigational plan. That half does not restate the protocol. Most of its common and example text is a sentence directing the reader to a named protocol section reproduced as an appendix, and the writing work is deciding what the report itself has to say because the protocol cannot: what actually happened, what changed, and what the study did about quality.
Ethics
The ethics section has three parts: two confirmations, of ethics committee review and of ethical conduct, and one brief description, of how consent was obtained.
Ethics committee review is confirmed for the protocol, its amendments, the information given to participants, and any recruitment advertisements, with the list of committees consulted placed in an appendix. The template's example text states that the protocol, its amendments, the consent form, the Investigator's Brochure, and other relevant documents were submitted to the committee and approved before the study was initiated, that amendments were approved before the changes were implemented, except for changes necessary to eliminate an immediate hazard to participants, and that, as applicable under local regulations, each pertinent competent authority also reviewed and approved the protocol and its amendments. The representative participant information sheet and a sample informed consent form, designated as the master versions, must be provided in the trial master file.
Ethical conduct is stated as common text: the study was conducted in accordance with the protocol and with consensus ethical principles derived from international guidelines, the template's bracketed set being the Declaration of Helsinki, the CIOMS international ethical guidelines, applicable ICH GCP guidelines, applicable ISO 14155 medical device guidelines, and other applicable laws and regulations. The set is revised as needed to match the protocol.
The report says briefly how and when consent was obtained in relation to enrolment, for example at pre-screening or at enrolment, and may point to where the consent form itself sits, the trial master file or an appendix. Where participants received an incentive or reimbursement, that is stated briefly with a reference to the protocol's financial disclosure section. The template's example paragraphs state that the nature of the study was explained and questions answered, that participation was voluntary, that a signed statement of consent meeting the applicable requirements was required, that sites were instructed to obtain written consent before enrolment and to document its date, that the person obtaining consent was instructed to sign the form too, that participants were re-consented to the current version during the study, and that a copy was given to the participant or their legally authorised representative.
Introduction
Section 1 carries the study rationale from the protocol, trimmed to the relevant parts if the protocol text is excessively long — the template's target is half a page. Any external guidelines followed are referenced, and where specific health authorities were consulted on the study design, a high-level summary is given that avoids commercially confidential material such as meeting minutes, which are better reserved for the Common Technical Document.
The introduction also gives any important new information since the study started, such as safety updates or an early termination, and explains any partial reporting, such as biomarker data to be provided later as addenda.
Objectives, endpoints, and estimands
Section 2 presents all objectives, endpoints, and estimands, if any. All objectives and endpoints — primary, secondary, and tertiary, exploratory, or other — are copied from the protocol or statistical analysis plan and any global amendments, and the recommended presentation is a table of objectives and endpoints with the estimand descriptions, including their rationales, set out below it. Estimands for the primary and key secondary objectives are defined in the protocol's objectives, endpoints, and estimands section; further estimands may come from the protocol's statistical considerations section or from the analysis plan. Where the study defined none, the estimand section is marked not applicable or removed.
An objective the report does not address may be dropped from the section along with its endpoint and estimand, but its absence should be explained in this section, in one of the three places where changes are recorded, or in both: changes in study conduct, changes in planned analyses before unblinding or database lock, and changes after unblinding and post-hoc analyses.
Study design and changes in conduct
Section 3.1 gives the study schema where there is one and a brief description of the overall design taken from the protocol. The summary is expected to be succinct and to name the interventions studied, whether the study was single- or multicentre, the treatment groups, the participant population, the type of study — blinded, open-label, parallel, cross-over — the type of control, the method of assignment, and the sequence and duration of the intervention periods. Diagrams and flow charts, or the overall-design text from the protocol synopsis, can be copied in. Any patient involvement in designing the study is summarised briefly with a cross-reference to the protocol.
The discussion of the design in Section 3.1.1 may reproduce the protocol's scientific rationale and its rationale for the chosen control groups, or take the streamlined route of one sentence pointing at the protocol's scientific rationale section. Special features of the study not already covered in Section 3.1 can be briefly summarised here, with references to the relevant figure and the protocol appendix: features such as interim analyses, safety data monitoring or special steering or evaluation committees, the handling of dropouts kept in the study, enrolling different types of participant at different centres, pharmacokinetic variables measured in selected participants, and data taken from electronic health records.
Section 3.1.2 covers changes in the conduct of the study. Changes in planned statistical analyses are excluded from it and go to Section 3.7.2 instead. What belongs here is a brief summary of substantial changes, often tabulated, since the detail sits in the protocol amendments appended to the report. Such changes include dropping a treatment group, changing entry criteria or dosages, adjusting the sample size, and changing assessment schedules. Because such changes require a protocol amendment, the section can cross-refer to the summary of amendment changes, often included in the protocol appendix, rather than duplicating it.
Substantial changes made to the conduct of the study without a corresponding protocol amendment are also described in the section. Where a change in conduct affects the interpretation of the study results, its possible implications are briefly described in the appropriate sections.
Investigators and administrative structure
Section 3.2, investigators and study administrative structure, places its required information in referenced appendices, for example sponsor and contract research organisation contact information alongside the list of investigators and other important study personnel, and the streamlined approach the template suggests is that the section contain only text directing the reviewer to those appendices; its example text adds that the protocol gives further information on the organisation of the study. No personal protected information and no patented measurement goes in this section.
Study population and intervention
The inclusion and exclusion criteria subsection gives a high-level description of the population — the template's common text says the study enrolled participants with a stated indication or population — and points to the protocol appendix for the specific inclusion and exclusion criteria. The removal subsection does the same for the criteria and procedures governing early discontinuation from the intervention or withdrawal from the study.
Interventions administered are copied from the protocol's own intervention and study-arm tables or text, describing what was given in each arm and each period, with route and mode of administration, dose, and dosage schedule. Where the investigational intervention is an add-on to a standard of care that may itself vary, the standard of care is described as the protocol describes it but clearly distinguished from the investigational intervention; other non-investigational interventions such as rescue medication or challenge agents are described separately under prior, concomitant, and post-intervention therapy, again clearly distinguished. The prior and concomitant therapy subsection itself points to the protocol for what was allowed and disallowed before, during, or after the intervention, and for the exceptions.
Per-participant batch numbers are no longer required for most submissions, but they must be available if a health authority asks for them. The report takes one of three options: list the manufacturing lot numbers in the report or an appendix, state that a listing is available on request, or point to an appendix listing which participants received which batch where more than one batch was used.
Measures to minimise bias are described with cross-references to the protocol. The method of assigning participants — central assignment or randomisation through an interactive voice or web response system — is described with a cross-reference to the protocol's assignment section. Masking is stated in terms of who was masked, choosing among assessor, investigator, caregiver, and participant, with a pointer to the protocol's blinding section, or the study is declared open-label. Other bias measures, such as independent adjudication of endpoints or a data safety and monitoring board, take their own subheadings and cross-references as needed. Compliance assessment methods are referenced to the protocol, and the subsection is deleted where it does not apply.
Assessments and procedures
The planned measurements and their timing are referenced to the protocol's schedule of activities and its assessment sections, and the collection of safety information — the evaluation, definitions, recording, and reporting of adverse events, serious adverse events, and other reportable safety events — to the protocol's safety assessments section.
Where the study's endpoints or measurements were novel or nonstandard, the appropriateness-of-measurements subsection identifies them and briefly describes how and why they were selected. Otherwise its example text states that the endpoints and measurements used were standard, considered reliable, and relevant to the objectives set out in the protocol. An additional summary of specific assessments is an optional subsection, deleted where it does not apply; subsections are added to it only where needed to describe information not available in the protocol, and the protocol should be referenced whenever possible.
Data quality assurance
Section 3.6 asks for the steps taken, at the investigative site or centrally, to ensure the use of standard terminology and the collection of accurate, consistent, complete, and reliable data. Such steps include training sessions, monitoring of investigators by sponsor personnel, instruction manuals, data verification, cross-checking, use of a central laboratory for certain tests, centralised ECG reading, and data audits, and the report notes whether investigator meetings or other steps were taken to prepare investigators and standardise performance. The database lock or cut-off date may be included here, and the subsections that follow are optional.
The subsections take that work in turn:
- Study monitoring — who monitored, that centres were visited at regular intervals and a visit log kept, that monitors reviewed protocol adherence, GCP compliance, and the completeness, accuracy, and consistency of the data, and that direct access to participant medical and laboratory records was permitted so that entries on the case report forms could be verified.
- Investigator training — that investigators were trained to comply with GCP and to conduct the study per the protocol, and that written commitments were obtained and are available on request.
- Laboratory procedures — inter-laboratory standardisation methods and laboratory quality assurance procedures, such as validation procedures and certificates, equipment calibration, and internal quality control or external quality assurance, are documented in the appendices if used, and laboratory manuals are not included. The example text states that a central laboratory analysed the samples and, where local laboratories were used, that their participation in quality control, quality assurance, and accreditation schemes was evaluated by the monitors. Studies with pharmacokinetic, pharmacodynamic, pharmacogenetic, biomarker, or immunogenicity work add text for those.
- Investigator responsibilities — that investigators were responsible for the data entered in the case report forms, documented their review and approval, verified validity and completeness, and retained the essential study documents.
- Clinical data management — who entered case report form data into which database, and whether quality checks were manual, electronic, or both.
- Quality assurance audits — where the sponsor used an independent internal or external audit procedure, it is mentioned here and described in the appendices, and audit certificates may be supplied there where applicable and available; audit reports need not be included. Where no audit was performed, the example text says so.
Where misconduct or serious GCP non-compliance occurred, it is documented in all relevant sections of the report, such as the relevant quality-assurance subsections, the protocol deviations section in Section 4.2, or both.
Quality tolerance limits
Where predefined quality tolerance limits were included in the protocol, Section 3.6.7 describes them: each limit's name, the parameter it was implemented to measure, and the rationale for judging the limit appropriate to cover the risk — the template's illustration is historical experience with successful studies in the same indication. It states that the limits were routinely assessed during the study, and whether values remained within them or there were important deviations. It also describes the quality management approach: the approach identified risks significant to participant safety or to the reliability of the study results, the plan used in the study documented the risks and the controls in place throughout the life of the study, and the limits were included in that plan.
Where a limit was exceeded, a general narrative may be included that covers how many deviations were detected, when they occurred and by how much they departed from the limit, what root cause analysis or assessment was carried out, what the root cause turned out to be, the actions taken, and the expected impact on participant safety and study objectives with a clear rationale for that assessment — with input from the relevant trial team members, such as the biostatistician, project manager, and drug safety representative. It also records whether the limit was adjusted after the analysis, for example because it was set too low at the start of the study; using quality tolerance limits is a learning process, so this is expected to happen occasionally.
In the template's example table, a limit was set at 12% for participants randomised who did not meet key inclusion or exclusion criteria; the observed value was 14% at the point when 55% of participants had enrolled; assessment of the individual cases revealed a consistent misinterpretation of one inclusion criterion; the protocol was revised to clarify that criterion and refresher sessions were held with all sites on compliance with the criteria; and the value was below the limit, at 11%, by the end of enrolment.
Where an important deviation from a limit rests on important protocol deviations, those deviations are described in the protocol deviations section, Section 4.2, and this section refers to it rather than repeating the detail. Where deviations are extensive, the details can move to an appendix, and the table describing important limit deviations and the remedial actions taken may be included as one.
Statistical considerations
The statistical analysis plan subsection directs the reader to the statistical analysis plan, or to the protocol where applicable, for all information about planned analyses — the planned analyses themselves, the comparisons and statistical tests, and the determination of sample size — without giving further detail of the planned methods in the section. Alternatively, it can reuse the brief high-level description suggested for the synopsis, extended to cover tertiary, exploratory, and other endpoints.
It is important that the timing of changes to the analyses, relative to blind breaking and the availability of outcome results, is well characterised. The report describes major changes between the analyses planned in the protocol and those in the analysis plan, such as a change in sample size or in the primary endpoint, and any changes made after the final analysis plan but before unblinding, with their rationale. Where all the changes were made by amendment to the plan or the protocol, the section can say so and point to the appendix; where there were none, it says that. Changes made after unblinding are briefly described separately in the subsection on changes following unblinding or database lock and post-hoc analyses, which is deleted where nothing applies.