Common to all phases of clinical trials is the necessity to define precisely who are eligible subjects. If healthy volunteers are required then a definition of 'healthy' is required. This definition may be relatively brief or complex depending on the substance under test. At the very early stage of the process it is very understandable that great care is taken in subject and, particularly, patient choice. In these situations, perhaps involving the very first use of the compound in humans, all the possible adverse eventualities have to be considered. These usually result in a very restricted definition for those that can be recruited.
Example - eligibility to a pharmacokinetic study - bioavailability of telithromycin
Bhargava, Lenfant, Perret et al. (2002) in a bioavailability study of the antibacterial telithromycin define the subjects to be recruited as follows: 'Male subjects aged between 18 and 45 y were recruited. Subjects were eligible for inclusion in the study if they were judged to be free of clinically significant disease on the basis of complete medical history and physical examination, standard clinical laboratory tests, a 12-lead electrocardiogram (ECG) (QTc4400ms) and vital sign assessments (heart rate 5 40 beats/min). Liver function tests, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) had to be strictly within the normal range'.
Example - eligibility to a Phase I trial - unresectable pancreatic cancer
In the Phase I trial of Muler, McGinn, Normolle et al. (2004), to be eligible patients were deemed to have unresectable pancreatic cancer, with or without metastases, based on helical computed tomography scan, endoscopic ultrasound and surgical consultation. In addition, their age was to be greater than 18 years, Zubrod performance status 42, estimated life expectancy of at least 12 weeks and adequate organ function defined as: absolute neutrophil count 51500cm3, platelets 5100000/cm3, serum creatinine <1.5mg/dL, bilirubin < 3 mg/dL, and AST < 5 times upper limit of normal. Further they had to have no prior history of abdominal irradiation or chemotherapy for pancreatic cancer.
Once the possibility of some activity (and hence potential efficacy) becomes indicated then there is at least a prospect of therapeutic gain for the patient. In this case, the investigators may expand the horizon of eligible patients but simultaneously confine them to those in which a measurable response to the disease can be ascertained.
Example - eligibility to a Phase II trial - gemcitabine in nasopharyngeal carcinoma
Foo, Tan, Leong et al. (2002) specify that patients were to have histologically confirmed undifferentiated carcinoma arising from the nasopharynx, bidimen-sionally measurable disease not within any prior radiotherapy fields, be between 18 and 75 years, with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) <2. In addition there were seven clinical chemistry limits that had to be satisfied before inclusion was possible. All patients were to receive 1250 mg/m2 gemcitabine on days 1 and 8 of a 21-day cycle.
In contrast to pharmacokinetic, Phase I and II trials, in a Phase III trial in which a prospective new therapy is under test, the eligibility should reflect if possible the (wider) patient pool in which it is to be eventually used should it prove effective. Thus the emphasis now is to define simple and minimal eligibility criteria that allow all types of patients into the trial in whom benefit from the therapy may be expected. Essentially these include all the patient types for which the comparator in the trial is the current standard. If the eligibility criteria are too narrow, then, however good the test treatment, the clinical implications will affect only small groups.
Example - eligibility to a Phase III trial - burn wound management
Ang, Lee, Gan et al. (2001), in a randomised trial to compare Moist Exposed Burns Ointment (MEBO) with conventional dressing, specified that eligible patients were all patients with partial-thickness burns. The exceptions were those of very young age and very old patients (<6 and >80 years), and those with chemical or electrical burns. Patients with severe burns are by their very nature emergency admissions, so minimal time must be spent in assessing eligibility as protocol treatment must commence immediately.
There are at least two further aspects of the eligibility requirements that are important. The first is that the patient indeed has the condition in question and satisfies all the other requirements. There must be no specific reasons why the patient should not be included. For example, in some circumstances pregnant or lactating women (otherwise eligible) may be excluded for fear of impacting adversely either on the foetus or the newborn child. The second is that all the therapeutic options for study in the Phase III trial are equally appropriate for the particular patient. Only if both these aspects are satisfied should the patient be invited to consent to participate in the trial.
There will be circumstances in which a patient may be eligible for the trial but the attending physician feels (for whatever reason) that one of the trial options is 'best' for the patient. In which case the patient should receive that option, no consent for the trial is then required and the randomisation would not take place. In such circumstances, the clinician should not randomise the patient in the hope that the patient will receive the 'best' option. To withdraw the patient from the trial if the alternative option is allocated may seriously bias the trial conclusions.
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