Specific issues in orphan disease clinical trials and rationale for trial design Studying orphan diseases presents specific challenges, specifically the limited number of patients available, wide geographic distribution and low priority for funding due to the perceived poor economic benefit. Patients are well informed about potential developments due to patient groups and internet based information(Tattersfield and Glassberg 2006) and may obtain potential treatments 'off label' making definitive research studies impossible. As LAM is rare, cohorts drawn from a wide area are required for studies to achieve adequate power. We have 15 years experience of LAM research and from our UK LAM database estimate there are approximately 120 patients in the UK. We are currently performing an open label study of Sirolimus in LAM and tuberous sclerosis (TESSTAL, a Study of The Efficacy and Safety of Sirolimus (Rapamycin) Therapy for Renal Angiomyolipomas in Patients with Tuberous Sclerosis Complex And Sporadic Lymhangioleiomyomatosis). This included six patients with LAM whom we found to be well motivated and will travel long distances for study visits (including Cornwall, Kent and Perth). Despite the known adverse effects of rapamycin six of eight eligible (i.e. with LAM and angiomyolipoma) patients invited took part in the study. The current study protocol has been designed as a simple protocol which is both inclusive of most patients with LAM and has a follow up which is similar to routine clinical care which we hope will facilitate recruitment. In addition the protocol is less demanding than that of the TESSTAL study. As most patients are known to us via our database or clinical contacts we expect recruitment to be complete within six months.