be undertaken to obtain local and, if appropriate, regulatory approval, is the development of the associated trial protocol. This document must be clear yet concise and contain all the elements necessary for all the members of the investigating teams to carry out their respective tasks. Thus, for any clinical trial, although the main features of the trial from design to analysis will be discussed in detail at the planning stage, the trial itself cannot be conducted unless the finalised plan is thoroughly documented. In broad terms, the range of features to be addressed in the trial protocol is indicated in Figure 3.1 although there may be additional requirements depending on the specifics of the actual trial to be undertaken, and the headings under which particular details fall will also vary with circumstance. For example, patient safety issues may be of paramount concern in one trial in which case this may warrant a dedicated section in the protocol. In others, this may not be the case so such issues may require only brief mention.
Figure 3.1 Major components of a clinical trial protocol
It is very difficult for any one person to think of every detail of all the elements that are needed for a particular protocol and so it is important to involve as broad a team as one can (certainly to include members from a range of disciplines) in the development process.
Further, although this may be mandatory within many situations, a review of the document by two or more experienced but independent peers together with an independent statistician (and other experts as may be relevant) is also advisable. Such a group should also review the data forms, whether paper, electronic or in a web‐based format, to ensure they are clear and that they encapsulate the key features, do not overburden the clinical teams or trial subjects with unnecessary detail yet enable the trial endpoint(s) to be unambiguously recorded for each subject.
Finally, the protocol should be dated, suitably bound in book form, and any subsequent amendments carefully documented. In the following sections, we address the individual sections of a protocol as detailed in Figure 3.1 and, wherever possible, give illustrative examples of how some of the sections have been phrased in activated protocols.
We cannot emphasise too strongly, that the protocol must be a high‐quality document, in both scientific and clinical terms, and needs to be written in clear language with careful highlighting of important issues. The protocol serves many purposes; for example, it gives an overview of the trial process from beginning to end, details the specific interventions, and how these are to be allocated. Importantly it guides the clinician through when and how assessments are to be made, and where necessary provides a step‐by‐step guide to administering the precise interventions stipulated.
Many of the issues introduced here will also be discussed in greater detail in later chapters.
3.2 Abstract
This section of the protocol is intended to give a concise overview of the aims of the clinical trial. The precise structure will depend on the features of the protocol that need to be highlighted. Of particular importance will be the type of subjects concerned, the interventions planned and the chosen design. This may take a structured format, as one might have when submitting the trial eventually for publication, or may be a bulleted list that is perhaps accompanied with a schema, such as that of Figure 2.1, summarising the design.
Example 3.1 Protocol SQGL02 (1999): Brimonidine as a neuroprotective agent in acute angle‐closure glaucoma (AACG)
This is an open‐labelled, randomized, active‐controlled prospective pilot study comparing the efficacy of Brimonidine 0.2% with Timolol 0.5% as a neuroprotective agent in preventing/reducing visual field defects in patients with acute angle‐closure glaucoma (AACG). 80 patients presenting with AACG at 4 centes (SGH/SNEC, TTSH, NUH & CGH) will be recruited into the study and randomized to Timolol or Brimonidine, in addition to the standard medical treatment and laser peripheral iridotomy (PI) for AACG. Baseline Humphrey visual fields program 24–2 will be performed after PI. The study medication will be continued for 1 month and the visual fields compared at the end of 4 months to determine if either group has better preservation of fields. If Brimonidine is found to be efficacious in preserving visual fields and hence offering neuroprotection, a larger prospective randomized clinical trial may be planned subsequently to follow.
This statement was followed by a sentence describing the trial objectives, very brief eligibility requirements of ‘unilateral attack of AACG and informed consent’ only, and finally, a schema illustrating key aspects of the design to be implemented. The extract very clearly summarises the main features of the planned trial.
An abstract within a scientific journal would not normally contain a schema of the trial design due to space limitations. However, within a trial protocol, this may well be very helpful as an overview of the trial. Thus SQCP01 (2006) trial of Example 3.2 below has an initial Summary page (as opposed to designating this as an Abstract) containing a structured review of Objectives, Eligibility, Method, and Design including an outline schema of their factorial trial. A more detailed schema is given in a later section of their protocol.
Example 3.2 Protocol SQCP01 (2006): Comparing speech and growth outcomes between two different techniques and two different timings of surgery in the management of clefts of the secondary palate
3.3 Background
Any individual or group concerned with answering an important clinical question by means of a clinical trial should be conversant with the medical speciality concerned and is likely to be expert within that discipline. Nevertheless, those planning a trial not only need to ensure they have the relevant team assembled but should still be prepared to seek outside assistance as appropriate. Thus, even at the early stages of formulating the research question, discussions with peers from relevant disciplines will always be valuable. Alongside this process, detailed reviews of the medical and related literature are required. These reviews can help formulate the research question itself, provide details on, for example, the safety of the interventions planned, and information on many other aspects of the intended trial. Once the question(s) is defined, a literature search may establish whether or not other trials have been conducted with the same or similar objectives and if so whether these either obviate the need for the trial in question or lead to some modification in its design.
The object of the background section within the trial protocol is to provide an in‐depth summary of how the proposed trial arose, with references to relevant published work, as well as the consequences for clinical practice and/or research once the trial results are known. Essentially this section would contain the information necessary for the Introduction that will be needed for the future research publication describing the trial results. Although it is difficult to be precise about the content the aim is to give an informed reader a clear rationale for justifying the importance and relevance of the clinical trial to be conducted. Thus, it must be persuasive enough to convince those who will be part of the formal approving
