Large simple trials (LSTs) are pragmatic, randomized clinical trials with minimal data collection protocols that are narrowly focused on clearly defined outcomes important to patients as well as clinicians. Their large sample size provides the adequate statistical power to detect small differences in effects between treatments in a situation where a moderate difference in an important outcome may be important. Additionally, LST's include follow-up that mimics normal clinical practice.
LSTs are particularly suited when an adverse event is very small or delayed (with a large expected attrition rate), when the population exposed to the risk is heterogeneous (e.g. different indications and age groups), when several risks need to be assessed in the same trial (e.g. risks of stroke and of myocardial infarction) or when many confounding factors need to be balanced between treatment groups. In these circumstances, the cost and complexity of a traditional RCT may outweigh its advantages and LSTs can help keep the volume and complexity of data collection to a minimum.
Outcomes that are simple and objective can also be measured from the routine process of care using epidemiological follow-up methods, for example by using questionnaires or hospital discharge records. LST methodology is discussed in Chapters 36 and 37 of the book Pharmacoepidemiology (Strom BL, Kimmel SE, Hennessy S. 5th Edition, Wiley, 2012), which includes a list of conditions appropriate for the conduct of a LST and a list of conditions which make a LST feasible. Examples of published LSTs are Assessment of the safety of paediatric ibuprofen: a practitioner based randomised clinical trial (JAMA 1995;279:929-33) and Comparative mortality associated with ziprasidone and olanzapine in real-world use among 18,154 patients with schizophrenia: The Zodiac Observational Study of Cardiac Outcomes (ZODIAC) (Am J Psychiatry 2011;168(2):193-201).
Note that the use of the term ‘simple’ in the expression ‘LST’ refers to data structure and not data collection. It is used in relation to situations in which a small number of outcomes are measured. The term may not adequately reflect the complexity of the studies undertaken.
|Annex 1.||Guidance on conducting systematic revies and meta-analyses of completed comparative pharmacoepidemiological studies of safety outcomes|