The Large Simple Study

This is a recently recognized alternative to stratification, pioneered by Peto. Large numbers of unselected patients are subjected to a single randomization. If enough patients are recruited, and if the randomization is truly unbiased, then the large sample sizes will allow all the potentially interacting variables (concomitant drugs, concomitant diseases, demographic variables, etc.) to balance out between the treatment groups.

The 'simple' part of this approach is that, in fundamental terms, the case report form can be very short. There is no need to collect lots of information about the patient's clinical condition because there is no use for these data. Trials of cardiovascular drugs, on an almost epidemi-ological scale, have been the most significant examples of this alternative approach. Literally tens of thousands of patients have been recruited under these protocols with case report forms having fewer than 10 pages for each patient. Dr Robert Temple (1997; Director of the Office of Drug Evaluation I, at FDA) has commented that it may even be possible to conduct large simple studies in treatment investigative new drug application (IND) situations, thus permitting the generation of efficacy data outside of orthodox 'Phase III' clinical trial programs. However, in this case the end-point would have to be just as simple, e.g. survival or death of the patient, during a documented period of observation; Kaplan-Meier analysis and other epidemiological approaches may also be applied to such databases.

Whilst the conditions under which large simple trials can provide efficacy data are fairly well worked out, it is important to consider whether (or which) tolerability issues can be precisely addressed in this way. If a tolerability factor (adverse event) relates to the efficacy variable of interest (e.g. a fatal adverse event in a patient survival study), then a simple case report form may provide relevant information. However, if the adverse event type is rare or unanticipated (e.g. the test drug causes unanticipated, significant anemia in 0.1% of patients, and the protocol and case report form do not collect hemoglobin values before and after treatment), then it is very likely that the adverse event will be missed. Large simple studies can thus create undue confidence in product tolerability ('thousands of patients were exposed to the agent during clinical trials').

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