Alkaptonuria (AKU) (OMIM#203500) is a serious, rare autosomal recessive disorder due to deficiency of homogentisate dioxygenase with resultant accumulation of homogentisic acid (HGA), occurring with a worldwide frequency of 1 in 250,000 . The accumulation of HGA results in progressively conversion and deposition to a melanin-like HGA-pigment in connective tissue, causing tissues to become rigid and brittle, and prone to degradation. This disease-specific pigmentary process is called ochronosis [2,3,4], which causes multiple systems to be involved resulting in varying phenotypes, characterised by severe premature spondyloarthritis, lithiasis, cardiac valve disease, fractures, muscle and tendon ruptures, and osteopenia [5, 6]. The disease is slowly progressing with a pre-symptomatic phase, apart from dark urine, until clinical signs and symptoms appear, usually when the patients are in their late twenties . For our research, the multifaceted aspects of the disease required multiple assessments so that the most appropriate endpoints could be defined. The result was the need to collect large amounts of data, meaning that studies that needed to be performed were complex. This also required compliance and willingness on the part of patients to ensure a successful study. At the same time, these aspects also require a large sample size for statistical power of the study despite the rarity of AKU, a significant challenge.
We were fortunate that a potential drug called nitisinone (NIT) was available to test in AKU. Until 1998 there was a lack of HGA-lowering disease-modifying therapy  when it was suggested that NIT, already in use as treatment of hereditary tyrosinaemia type 1 (OMIM 276700) , could also decrease HGA . NIT inhibits the enzyme p-hydroxyphenyl-pyruvate dioxygenase (HPPD) (EC:220.127.116.11), thereby decreasing the accumulation of HGA. [10, 11]. Ochronotic pigment develops from HGA; therefore, a decrease in HGA could decrease pigment, and consequently the morbidity of AKU. Initial studies employed an oral dose of 2 mg daily even though a full dose–response profile was never undertaken, and adopted for the first NIT interventional study ; 20 NIT-treated patients were compared with 20 controls, employing lateral rotation of the hip as the primary outcome, with the study reporting inconclusive. As a result, a consortium of European investigators came together to conduct a European Commission-funded study called the Suitability of Nitisinone in Alkaptonuria 2 (SONIA 2), a 4-year phase 3 NIT outcomes study in AKU. Our experiences in identifying and overcoming barriers in this SONIA 2 study, before starting the study during the preparatory phase, during the conduct of the study and then post-study activities to enable regulatory approval of the first disease-modifying therapy for adults with AKU is described in greater detail here.