3.7 Eligibility
Depending on the disease or condition in question, the precise mechanisms for determining which individuals are eligible for the protocol will vary considerably. The protocol should delineate with care the inclusion and exclusion criteria. For example, a general clinic may see many potential patients of a particular type, who will then need to be screened to determine whether they are truly eligible for the trial. In other situations, a clinic may be more specialised in nature so that everyone coming to the clinic has been pre‐screened and is likely to satisfy the requirements of the protocol. The proportion of eligible subjects will vary from trial‐to‐trial. In Protocol UKW3 (1992), the number of operable children with renal (Wilms’) tumours was likely to be less than half of those presenting with the disease.
Example 3.12 Protocol UKW3 (1992): Preoperative chemotherapy in Wilms’ tumour
4. ELIGIBILITY
All patients with renal tumours should be registered with the UKCCSG by the participating centres.
The following patients are eligible for this study:
Patients over 6 months and under 16 years at the time of diagnosis. Clinical and radiological evidence of unilateral Wilms’ tumour considered to be operable – see section 7.
No detectable distant metastases.
No previous treatment for Wilms’ tumour
Although criteria for eligibility to a trial can always be phrased as ‘Inclusions’, it may be appropriate sometimes to highlight some aspects of (non) eligibility more forcibly as ‘Exclusions’. Thus, in a trial of a new oral contraceptive rather than phrase an eligibility condition as, for example: ‘Women who are neither pregnant nor breastfeeding’; one might state under a distinct heading of Exclusions: ‘Women who are pregnant or breastfeeding’. Then the clinical team can more readily identify those individuals who are, or are not, eligible. Therefore, this section of the protocol is often better presented as a series of (short) bullet points rather than as prose. Further, it is also important to list these in as useful sequence as possible, perhaps one that reflects closely the logistics of the clinical examination process. For example, if there is an age restriction on those patients who can enter the trial, this might be at the top of such a bulleted list as age is easily determined in most circumstances; for a patient outside the permitted range, there would be little point in checking further inclusion or exclusion criteria especially if these involve an invasive examination which is not part of routine clinical practice. Also high on the list might be ascertaining whether or not all the protocol treatment options are suitable for the potential trial recruit. This saves time and inconvenience for both the would‐be trial patient and the protocol team. One example is the weight limit of 140 kg in the PRESSURE (2000) protocol although it is listed as last amongst the specified Exclusion criteria. In this case, its low position within the list may well be entirely justified, since such a bodyweight is rare amongst the types of patients concerned.
Example 3.13 Protocol PRESSURE (2000) Section 6.2: Pressure‐relieving support surfaces: a randomised evaluation
6.2 Exclusion criteria
Patients will be excluded from the study if any of the following criteria apply. They:
– have pre‐existing Grade 3, 4 or 5 (Table 1a) pressure sore on admission
– have participated in this trial during a previous admission
– are an elective surgical patient with a planned post‐operative admission to ICU
– are an elective surgical patient admitted more than 4 days before surgery
– sleep at night in a chair
– weigh >22 stones/140 Kg (upper weight limit for overlay mattress)
a Table 1 referred to here is similar to that of Figure 4.2 in the next chapter.
In addition to the Exclusion Criteria, in the PRESSURE (2000) protocol, there were rather complex Inclusion Criteria as three general types of patients were to be included. These patients were those having an admission to one of the designated hospital wards, and who were also one of the following three types: (i) Acute, (ii) Elective with existing pressure sore or with reduced mobility, and (iii) Elective with neither a pressure sore nor with reduced mobility.
In the past, protocols tended to be restrictive about the patients admitted to trials and would focus on good‐prognosis patients. Modern trials increasingly adopt the perspective that patients are eligible provided the clinician regards all the options for treatment within the protocol as potentially suitable for the patient under consideration, and provided the clinician acknowledges that it is objectively unclear as to which option is preferable. Thus, fewer eligibility criteria now specify an upper age limit, but are more likely to emphasise that the patient should be fit enough to tolerate side effects and toxicity.
3.8 Randomisation
There are two aspects of the randomisation process that need to be described in the protocol. One is the structural features of the design while the other is the more procedural aspects of how patients will be randomised and hence allocated to a specific intervention. However, as we will discuss in Chapter 5, there is a difficulty in that if full details of a block based or other restricted randomisation schemes are made explicit in the protocol itself then the objectivity of the randomisation process may be compromised. So, we advise that such details are held in a confidential memo by the statistical team which is securely stored in the trial office files and, if need be, shared with the approving authorities but not with the clinical members of the protocol team until trial recruitment is complete.
3.8.1 Design
Although Protocol AHCC01 (1997) referred in the statistical methods to a 2 : 1 : 2 randomisation between placebo (P), tamoxifen 60/mg/day (TMX60) and TMX120 no reference to ‘randomisation in blocks’ was made. Nevertheless, the eventual trial publication of Chow, Tai, Tan, et al. (2002) stated:
Randomization was performed in balanced blocks of 5, stratified by center, and corresponding to P, TMX60, and TMX120 in the respective ratios of 2 : 1 : 2.
In contrast to randomised blocks, the PRESSURE (2000) trial used a minimisation method (see Chapter 5) with the four factors recruiting centre, skin condition, clinical specialty of the admitting hospital ward, and whether an acute or elective admission.
Just as we have suggested that it is desirable not to reveal the block size, the precise amount of randomness set in a minimisation method should not be revealed within the protocol itself, but should be documented in a separate memo by the statistical team.
Example 3.14 Protocol PRESSURE (2000) Section 7.2: Pressure‐relieving support surfaces: a randomised evaluation
7.2 Mattress Allocation Method
Allocation to treatment will be by minimisation and with respect to the factors listed in Table 4.
Table 4 Minimisation