Anatomy of a Clinical Trial Protocol

Drafting a research protocol for a clinical trial starts from a concrete clinical hypothesis, to be verified or confuted through the conduct of the study.

The trial generally tests an hypothesis using an investigational medicinal product (IMP), a drug, a medical device, food supplement or diagnostic tool on a specific population of patients. The design of the trial is generally aimed at assessing the efficacy and safety of a new IMP, for registration and authorization purposes (phase I to III), or to confirm or confute previous evidence and acquire new, real world data on the product (post-market, phase IV). 

Non profit and investigator-initiated trials may also have aims that differ from the mere regulatory purpose, with a special focus on the implementation of clinical practice. For these studies the protocol design is especially based on scientific evidence, clinical experience and observation. Furthermore, these studies could be designed with the absence of control groups, randomization and blinding, for a leaner conduct, easier to carry out in the context of no-profit settings.  

Part I - The study background

In the first part of a clinical study protocol, an extensive introduction is provided, as an overview on the topic of the study. The introduction is aimed at contextualizing the trial within the scientific landscape concerning the clinical condition and the therapy, investigated within the study. A background is drafted, to describe the existing knowledge for this study, the importance of the topic and the clinical innovation that the trial will lead to. Pre-existing literature is critically evaluated to define the outcome measures, the objectives and the selection criteria of the study population. The primary and secondary endpoints are clearly stated, and the whole trial design is aimed to pursue these objectives.

An accurate and detailed risk-benefit analysis is provided, to describe possible drawbacks derived from the involvement in the investigation, side effects and adverse events already known in relation to the IMP. 

Independently from the study design or the investigational phase, the research methodology must be accurately and clearly explained in the second section of the protocol.  This will ensure a univocal comprehension by the Review Board, the investigators, the sponsor and all the stakeholders involved in the trial. The protocol represents the reference document for the subsequent completion of all the other trial-related documents (e.s. investigator’s brochure, trial master files, monitoring diaries, case report forms). Furthermore, methodology design must always adhere to the Good Clinical Practice principles, so that the trial conduct will be in compliance with international standards for clinical investigation.


Part II - Study design and methodology

Study design is the most accurate and relevant process to carry out in advance and report in the study protocol. Nowadays, several study concepts are available, with many alternative designs (factorial trial, cross-over trial), which represent some valuable options for a faster and powerful persecution of the study endpoints. 

The study design should always be consistent with the advocated aims and hypothesis.

Concerning methodology, some relevant aspects must be described in detail:

  • Selection criteria for study population (inclusion and exclusion criteria)
  • Study drop-out criteria, for the interruption of study participation 
  • Baseline evaluation of the participants, at the time of the enrollment
  • Therapeutic protocol and IMP characteristics
  • Clinical evaluation tools during and after the treatment, with clear timelines and endpoints 

The correct selection of patients in the study avoids possible selection bias.

Part III - Statistical analysis plan and additional information

Another consistent part of the protocol is represented by the Statistical Analysis Plan (SAP), where the statistical methods for data analysis are described. Data series that will be collected should be clearly identified, and the data type understood. Bassing on these information, the basic data processing procedures are usuaally reported, describing the measures of tendency and dispersion. Furthermore, models of inference are described, to meet the study design specifications (longitudinal analysis, epidemiological measures, or regression analysis, to list a few). In this section, also the sample size calculation and other accessory analytical methods for data selection and processing are provided. 

Monitoring procedures are also illustrated in full, to ensure a systematic approach to source data verification, compliance of the procedures and data management. A monitoring plan and quality assurance plan can be  attached to the protocol.

In the last part of the study protocol, additional information concerning ethical conduct, privacy in handling of data, data transfer protocols, financial support and funding allocation should be always reported. 

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