Trials in Alzheimer's disease
Developing a medicine for Alzheimer's disease raises questions of clinical trial design across the stages of the disease, which the European Medicines Agency set out in a revised guideline released for public consultation in 2016 and in a revised guideline adopted in 2018.
How the guideline was revised
On 1 February 2016 the European Medicines Agency released a revised guideline on medicines for the treatment of Alzheimer's disease and other dementias for a six-month public consultation, inviting comments by 31 July 2016 using the template provided. The agency considered dementia a key public health priority and followed a multi-stakeholder approach to facilitate the research and development of more effective medicines.
The draft took into account comments received at the agency's November 2014 workshop on the clinical investigation of medicines for the treatment of Alzheimer's disease. The workshop brought together a wide range of stakeholders, including patient representatives, regulators, the pharmaceutical industry and independent experts. It aimed to let the agency consider, during the revision, the most up-to-date scientific developments in understanding and treating the disease and the views of experts in the field. The draft also built on the agency's scientific advice on a number of specific development plans for Alzheimer's disease in the preceding years, and on the qualification of several biomarkers for selecting patients in clinical trials. Comments received during the consultation were to be taken into account in finalising the guideline.
By 28 February 2018 the agency's Committee for Medicinal Products for Human Use (CHMP) had adopted a revised guideline on clinical studies for medicines that target Alzheimer's disease, effective from 1 September 2018. The guideline aims to guide the development of medicines across all stages of the disease.
Before this revision, the agency organised a workshop for patients, academia, regulators, representatives of the pharmaceutical industry and independent experts, to ensure that the agency was informed of the most up-to-date scientific developments in understanding and treating the disease. It complemented the workshop with a series of meetings with developers of medicines intended to slow disease progression, to discuss the issues encountered in their clinical trials. The 2018 guideline also builds on the scientific advice the agency gave developers on specific products and methodologies, such as the qualification of biomarkers for use in clinical trials and a longitudinal model describing changes in cognition in patients with mild or moderate Alzheimer's disease.
Trials in earlier disease stages
Recent progress in understanding the pathophysiology of Alzheimer's disease suggests that the biological changes associated with the disease start as early as 10 to 20 years before clinical symptoms appear. The agency therefore held in 2016 that experimental medicines should be evaluated in earlier disease stages, as certain treatments may be more effective at that stage than later in the illness. By 2018, for the same reasons, many experimental medicines were being investigated in earlier disease stages.
What the guideline addresses
The 2016 draft specifically addresses:
- the impact of new diagnostic criteria for Alzheimer's disease, including early and even asymptomatic disease stages, on clinical trial design
- the choice of parameters to measure trial outcomes, and the need for distinct assessment tools for the different disease stages, which differ in signs and symptoms, in changes over time and in severity
- the potential use of biomarkers and their temporal relationship with the different phases of the disease at different stages of medicine development (for example mechanism of action, use as a diagnostic test, enrichment of study populations, stratification of subgroups, and safety and efficacy markers)
- the design of long-term efficacy and safety studies
Among other things, the 2018 guideline addresses:
- the impact of new diagnostic criteria for Alzheimer's disease, including early and even asymptomatic disease stages, on clinical trial design
- the factors to be considered when selecting parameters to measure trial outcomes at the different disease stages
- the potential use of biomarkers in the various stages of medicine development
- the design and analysis of efficacy and safety studies