Clinical study protocols

A clinical study protocol is the document a clinical trial is approved and conducted on. This branch divides it by what a writer of the protocol has to settle: the requirements and structure its content answers to and what that content costs a trial, how its development is run and patient input gathered, what it says about the trial and its design, how it is peer-reviewed and amended, and how another country's rules or an investigator's own research shape it. It leaves the device counterpart to clinical investigation plans for medical devices, the report that answers to the protocol to clinical study reports, the design and analysis of an interventional trial and its statistical analysis plan to designing and analysing clinical trials, quality by design across a sponsor's whole clinical development and quality tolerance limits to good clinical practice and trial quality, posting the protocol with a trial's results to registering a trial and posting its results, and the method of any review among several reviewers to running a review among several reviewers.

• Where a protocol's content requirements come from — the guidances that each set part of the content, from ICH E6, E9 and E17 to Annex I of the EU's clinical trials legislation, what the SPIRIT statement, the ICH E6(R3) contents list and a US review board ask for, and the NIH-FDA and TransCelerate templates that fill the space they leave
• The structured protocol and ICH M11 — what ICH M11 is and why protocols are being restructured, its status over time and its fit with the TransCelerate template, authoring to the template, moving scattered narrative into defined content, transparency readiness, aligning the protocol with the report, and what compliance with the template can show
• What protocol complexity costs a trial — what makes a protocol complex and how its content has grown, what complexity does to recruitment and retention, to participants and sites, to the data and to amendments, and limiting it by agreeing what is critical, down to simplicity in the emergency department
• Running protocol development — why the protocol needs a writer, maturing the study concept before the full protocol, where the writer's part stops, protocol writing teams in research institutions and the approval process they work through, timelines, software tools, templates and checklists, and compressed timelines in practice
• Patient input into the protocol — why protocols are expected to include patient input, what patients weigh in a trial, asking for their input at the start of design, what a patient advocate can answer about a protocol, recording the input in the protocol, and what involvement changed in a spinal muscular atrophy programme
• Drafting the protocol — what a protocol is and its sections, planning from the decision the study has to inform, the rationale, objectives, population and eligibility, endpoints, design and schedule of assessments, control groups and statistics, checking the key sections, the case report form, managing built-in redundancy, protecting participants, and wording nothing a site could read two ways
• Building the protocol around the estimand — why the protocol carries estimands, the clinical question of interest, the objectives, estimands, endpoints and statistical considerations the framework shapes, the two public templates, example protocols, and where to look when a template is silent
• Describing an adaptive design — what an adaptive design changes and how the protocol describes its adaptations
• Writing a master protocol — why master protocol designs arose, defining one and its kinds, dividing the content between the master protocol and its sub-protocols, choosing the structure, registering, submitting and reporting the study and running its development, with two worked protocols
• Describing decentralised components — the move from rescue tools to designed-in components, what ICH E6(R3) Annex 2 asks the protocol to describe and the guidance from ACRO, the EU and the FDA, scoping each component by why, who, what, where, when and how, and what the protocol says about each kind of component
• Drawing the study schema — what a study schema is for and the designs it can show, who reads it, laying the study out as a timeline and what the timeline shows, and labelled icons that carry the design across languages
• Quality by design in a trial protocol — what quality means in a clinical trial, the protocol as its blueprint, data priorities, critical-to-quality factors and the risks to them, the design space and the tolerances stated in the protocol, the quality management plan, planning time, templates and checklists, and the writer's place in the quality cycle
• Designing a trial for lower emissions — the travel, sample, data and supply decisions a protocol can change, what the NIHR carbon reduction guidelines recommend, digital solutions that shorten a trial or shrink its cohort, the regulatory acceptance of a smaller trial, and weighing the options with a carbon calculator
• Peer-reviewing a clinical trial protocol — what protocol peer review is, the writer and the stakeholders, the review team, the kick-off meeting, the review cycle and its timeline, version control and document management systems, briefing and training the reviewers, making and resolving comments, and the crucial elements to check section by section
• Amending a protocol — matching a change to its urgency, from an urgent safety measure through a substantial change to a minimal change kept in a note to file, how often protocols are amended, what amendments change and why, the time an amendment adds, and the amendments that could be avoided
• Placing a study under another country's rules — why sponsors place studies abroad and what to weigh first, what doing so does to the documents, designing to a national law that requires or prohibits a study and to national requirements for bioequivalence, biosimilar and orphan drug studies, and vocabulary that commits a study to a national regulatory category
• Writing a protocol for investigator-led research — the protocol an investigator writes for an ethics committee or review board and perhaps a funder, the research team behind it, its elements from the title, summary and research question through the methods, analysis, safety and data management to duration, dissemination, investigators, resources and ethics, and the common problems and the final review