3.14 Trial forms
As we recommended earlier, since recording the patient data is integral to successful trial conduct, inclusion of the trial forms into the protocol itself is often desirable, even when they are quite simple in structure. However, if these are web rather than paper‐based how these are to be presented to any protocol review committee may depend on local circumstances.
The forms should be developed in parallel with the protocol, and may (depending on local regulations) have to be submitted for approval with the trial protocol itself in any event. The number, structure and complexity of the forms required for a trial will be very trial‐specific but, as a minimum, there will be forms containing subject‐specific information relevant to the registration and randomisation process including the intervention assigned, those encapsulating eligibility and other baseline characteristics of those recruited, and a form for the endpoint assessment. In almost all circumstances there will be many more than this and most trials will include special forms for recording details of, for example, any surgical procedures undertaken or unexpected adverse events should they arise.
In general terms, the forms for the clinical trial should focus on essential detail that is necessary to answer the question(s) posed by the design and should not be cluttered with irrelevant items. This focus keeps the clinical teams aware of the key issues and takes them less time than having to record inessential details. Consequently, there are likely to be fewer errors. The completed form also becomes easier to check if there are fewer items and thereby reducing the data management processes and speeding up checking. In this way, any problems remaining can be fed back to the clinical teams more rapidly – which again reduces the workload at the clinical recruiting centre. The briefer the forms, and indeed the simpler the trial procedures, the easier it becomes for collaborators and the more rapidly they are likely to recruit the patients required. But this must be balanced against the need to ensure that the forms do contain all the necessary information that will be required for the analysis. However, the experience of many groups indicates that most trials collect far too much information that is then never analysed nor reported on.
Forms may need to include patient management details, such as the date of the next follow‐up visit, or to confirm if an action has been taken such as the despatch of a laboratory specimen or the completion by the patient of a quality‐of‐life questionnaire. It is best if these are kept to a minimum, and located in a distinct part of the form (perhaps the last items) so that when the forms are received for processing at the trials office these items can easily be distinguished from variables that must be included in the trial database.
3.15 Appendices
As often as not, a protocol will almost certainly have to contain Appendices. For example, in many cancer clinical trials toxicity is a major concern so that the criteria for reporting adverse events as recommended by the National Cancer Institute (2003) will often be reproduced.
As informed consent is such a critical process, reviewing committees will almost certainly wish to see the proposed patient information sheets and the consent forms to be used. Figure 3.2 gives part of the patient information provided and Figure 3.3 the corresponding consent form for the COMPLIANCE (2015) trial protocol described by He, Tan, Wong, et al. (2018) concerning compliance with medication in women with breast cancer.
Figure 3.2 Part of the Information Sheet utilised in the multicentre COMPLIANCE (2015) trial in patients with breast cancer.
Source: COMPLIANCE (2015).
Figure 3.3 facilitates the consent approval process in cases when a prospective patient may not speak, in this case, English, is illiterate, or is otherwise compromised.
3.16 Regulatory requirements
3.16.1 Protocol amendments
Although great care should be taken in preparing the trial protocol, once the approved trial has opened for patient recruitment and is in progress, unforeseen circumstances may arise that impact on what is contained within the protocol. Such circumstances could range from the relatively trivial to the very serious. At one extreme, perhaps the packaging of a study drug is changed by the supplying pharmaceutical company without change to the potency or any significant aspects. At the opposite extreme, perhaps unanticipated and serious reactions in some patients occur, raising concerns about whether the trial medication is safe and consequently impacting on whether or not the trial should continue as originally planned. The consequences of the latter might for example either result in restricting the trial entry criteria by identifying those who are likely to be vulnerable and making them no longer eligible, or reducing the dose should the anticipated reaction occur. Both of these represent an important change to the protocol. The protocol would then have to go through a reapproval process. In contrast, the minor change in packaging may only require informing the authorities of this fact. Of course, in this instance, if the protocol has to be changed for any other minor reason(s), then it would be prudent to make this change(s) at the same time.
Figure 3.3 Consent form designed to obtain assent from a patient to be randomised in the multicentre COMPLIANCE (2015) trial in patients with breast cancer.
Source: COMPLIANCE (2015).
Since protocol modifications are not infrequent, it is wise to keep the protocol as concise as possible; exclude all irrelevant detail; ensure main sections start on new pages; ensure page breaks do not break paragraphs (perhaps not important in the Background but may be critical if describing details of an intervention); number sections, tables and figures in such a way as to minimise the need for future renumbering or repagination of the protocol. Without such precautions, there can be severe consequences if any additions or modifications happen to occur in sections from the early pages of the protocol.
3.17 Guidelines
As we have indicated GCP, set out in ICH E6 (R2) (2016), will dictate in full the items that are mandatory for such a protocol. Similarly, the SPIRIT 2013 statement provides recommendations for a minimum set of scientific, ethical and administrative elements that should be addressed in a clinical trial protocol. It is particularly important, and especially for clinical trials seeking formal registration of a new product, that investigators check local, national and even international requirements for what has to be included in the protocol itself. The definition of what is a ‘protocol’ given by Day (2007) and slightly amended in our Glossary includes the phrase ‘important details’ so it is imperative to check the current status of exactly what current versions of the guidelines are suggesting as they are continually changing. For example, the ICH E6 (R2) (2016, Section 6) specifies for protocols sections on: Direct access to source data/documents; Quality control and quality assurance; Data handling and record keeping: Financing and insurance which we do not include in Figure 3.1. In this document