Futility studies

Phase III studies of disease-modifying agents for neurodegenerative disorders generally require hundreds of patients to be followed for at least 2 years at a cost of millions of dollars. No matter how promising an agent may appear in preclinical studies and animal models, preliminary evidence that the treatment is likely to be helpful in patients (proof-of-concept) and that it is reasonably safe is essential before asking patients to accept risk and making the necessary investments in human resources, time, and money. In this issue of Neurology, three articles discuss futility studies, a clever method of dealing with the trade-off between investment risk and clinical promise.^1–3 The requirements to definitively demonstrate clinically meaningful benefits and long-term safety demand long duration, large sample size Phase III studies. Proof-of-concept studies have more flexibility in their design and endpoints that may allow for smaller and more cost effective studies.

In multiple sclerosis (MS) research, the need for proof-of-concept studies has often led to the use of MRI measures of disease activity, especially gadolinium enhancing lesion incidence, as primary endpoints. Serial assessment of gadolinium enhancing lesions can demonstrate that an agent reduces inflammatory disease activity with as few as 20 patients followed for 3 to 6 months. Similar biomarkers are actively being sought for other neurologic diseases with variable degrees of success. It is not sufficient to identify biomarkers that correlate with disability and are reliably quantified. For such biomarkers to be advantageous, they also need to be more sensitive to therapeutic effects than the clinical measures they …