Multiple sclerosis (MS) is a progressive, disabling disorder of the brain and spinal cord that affects approximately 100,000 people in the UK and 2.5 million worldwide [101]. Most patients with MS experience two phases of the disease: early, relapsing–remitting MS (RRMS), due to episodes of generally reversible inflammation-mediated nerve damage (relapses) and late, secondary progressive MS (SPMS), which affects 60% of patients. This occurs after 10–15 years and causes accumulating and irreversible disability due to nerve degeneration. The destruction of the CNS results in progressive difficulties with walking, balance, vision, urinary control and cognition. Total societal costs are high, estimated to be up to GB£30,000/patient/year [1–3]. Over the last 20 years, a variety of increasingly powerful drugs have been tested and demonstrated to reduce relapse rate in RRMS by up to 70% [4]. Although rare but serious side effects have emerged, these compounds are now in clinical use. The use of MRI was important in their development and is discussed below. However, unlike RRMS, there is no proven treatment for SPMS to slow, stop or even reverse its progression. Unsurprisingly, a number of drugs used in RRMS have been trialed in SPMS, but without success, presumably because of changing biology. Using the classical parallel arm control/active trial design, it can take >10 years from a Phase I trial inception to Phase III trial finish [5]. Over the last two decades, more than 4500 SPMS patients have completed major Phase III trials, with trial durations of 2–3 years. The overwhelming conclusion is that all these have been negative, with the few positive signals actually observed being due to coenrollment of a more transitional RRMS/SPMS population or a subscore of the primary outcome being positive. The current consensus therefore, is that SPMS is most likely to respond to a neuroprotective strategy, and indeed there are a number of promising candidate drugs to test. The clear challenge therefore is to test multiple drugs simultaneously, in a timely and efficient manner, whilst preserving trial integrity. This article will discuss pathology, outcome measurement, alternative trial design approaches to the problem and end with a worked example.